NZ617142B2 - Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor - Google Patents
Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor Download PDFInfo
- Publication number
- NZ617142B2 NZ617142B2 NZ617142A NZ61714212A NZ617142B2 NZ 617142 B2 NZ617142 B2 NZ 617142B2 NZ 617142 A NZ617142 A NZ 617142A NZ 61714212 A NZ61714212 A NZ 61714212A NZ 617142 B2 NZ617142 B2 NZ 617142B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- crbn
- cancer
- antibody
- drug
- compound
- Prior art date
Links
- 102100018530 CRBN Human genes 0.000 title claims abstract description 209
- 108060001884 CRBN Proteins 0.000 title claims abstract description 209
- 201000011510 cancer Diseases 0.000 title claims abstract description 172
- 200000000018 inflammatory disease Diseases 0.000 title description 15
- 239000011780 sodium chloride Substances 0.000 claims abstract description 104
- 150000003839 salts Chemical class 0.000 claims abstract description 103
- 239000012453 solvate Substances 0.000 claims abstract description 87
- 239000003814 drug Substances 0.000 claims abstract description 86
- 229940079593 drugs Drugs 0.000 claims abstract description 74
- 230000014509 gene expression Effects 0.000 claims abstract description 67
- 230000004044 response Effects 0.000 claims abstract description 65
- GOTYRUGSSMKFNF-UHFFFAOYSA-N Lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims abstract description 63
- 229960004942 lenalidomide Drugs 0.000 claims abstract description 63
- UEJJHQNACJXSKW-UHFFFAOYSA-N Thalidomide Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229960003433 Thalidomide Drugs 0.000 claims abstract description 44
- UVSMNLNDYGZFPF-UHFFFAOYSA-N Pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 claims abstract description 43
- 229960000688 pomalidomide Drugs 0.000 claims abstract description 43
- 239000012472 biological sample Substances 0.000 claims abstract description 28
- 206010012818 Diffuse large B-cell lymphoma Diseases 0.000 claims abstract description 23
- 102000004965 antibodies Human genes 0.000 claims description 216
- 108090001123 antibodies Proteins 0.000 claims description 216
- -1 3-(5-aminomethyl oxo-4H-quinazolinyl)-piperidine-2,6-dione Chemical compound 0.000 claims description 70
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 60
- 150000001413 amino acids Chemical class 0.000 claims description 22
- 210000003719 B-Lymphocytes Anatomy 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 239000000032 diagnostic agent Substances 0.000 claims description 2
- RSNPAKAFCAAMBH-UHFFFAOYSA-N 3-(5-amino-2-methyl-4-oxoquinazolin-3-yl)piperidine-2,6-dione Chemical compound CC1=NC2=CC=CC(N)=C2C(=O)N1C1CCC(=O)NC1=O RSNPAKAFCAAMBH-UHFFFAOYSA-N 0.000 abstract 2
- 150000001875 compounds Chemical class 0.000 description 209
- 239000000203 mixture Substances 0.000 description 161
- 210000004027 cells Anatomy 0.000 description 102
- 201000010099 disease Diseases 0.000 description 95
- 102000004169 proteins and genes Human genes 0.000 description 78
- 108090000623 proteins and genes Proteins 0.000 description 78
- 206010028980 Neoplasm Diseases 0.000 description 72
- 235000018102 proteins Nutrition 0.000 description 70
- 239000000427 antigen Substances 0.000 description 56
- 108091007172 antigens Proteins 0.000 description 55
- 102000038129 antigens Human genes 0.000 description 55
- 239000002552 dosage form Substances 0.000 description 48
- 206010035226 Plasma cell myeloma Diseases 0.000 description 45
- 230000027455 binding Effects 0.000 description 43
- 239000003795 chemical substances by application Substances 0.000 description 43
- 238000002560 therapeutic procedure Methods 0.000 description 42
- 239000000090 biomarker Substances 0.000 description 41
- 230000000694 effects Effects 0.000 description 41
- 235000001014 amino acid Nutrition 0.000 description 40
- 229920001184 polypeptide Polymers 0.000 description 39
- 108020004999 Messenger RNA Proteins 0.000 description 37
- 229920002106 messenger RNA Polymers 0.000 description 37
- 239000000523 sample Substances 0.000 description 37
- 206010025323 Lymphomas Diseases 0.000 description 33
- 239000004480 active ingredient Substances 0.000 description 33
- 201000009251 multiple myeloma Diseases 0.000 description 30
- 206010025310 Other lymphomas Diseases 0.000 description 29
- 210000001519 tissues Anatomy 0.000 description 29
- 101700047660 IRF4 Proteins 0.000 description 27
- 102100013274 IRF4 Human genes 0.000 description 27
- 150000007523 nucleic acids Chemical class 0.000 description 26
- 210000004369 Blood Anatomy 0.000 description 25
- 239000008280 blood Substances 0.000 description 25
- 206010029592 Non-Hodgkin's lymphomas Diseases 0.000 description 24
- 108020004707 nucleic acids Proteins 0.000 description 23
- 239000008194 pharmaceutical composition Substances 0.000 description 23
- 108010045030 monoclonal antibodies Proteins 0.000 description 22
- 206010024324 Leukaemias Diseases 0.000 description 20
- 102000005614 monoclonal antibodies Human genes 0.000 description 20
- 230000002401 inhibitory effect Effects 0.000 description 19
- 239000007787 solid Substances 0.000 description 18
- 210000004881 tumor cells Anatomy 0.000 description 18
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 17
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 description 17
- 101700019301 CUL4A Proteins 0.000 description 17
- 102100015948 CUL4A Human genes 0.000 description 17
- 239000002246 antineoplastic agent Substances 0.000 description 17
- 239000002585 base Substances 0.000 description 17
- 238000000034 method Methods 0.000 description 17
- 230000004083 survival Effects 0.000 description 17
- 206010008943 Chronic leukaemia Diseases 0.000 description 16
- 108091008117 polyclonal antibodies Proteins 0.000 description 16
- 102100006400 CSF2 Human genes 0.000 description 15
- 102100015947 CUL4B Human genes 0.000 description 15
- 101700070193 CUL4B Proteins 0.000 description 15
- 102100013030 DUS3L Human genes 0.000 description 15
- 101700026792 DUS3L Proteins 0.000 description 15
- 102100007245 GSK3B Human genes 0.000 description 15
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 15
- 102000018358 Immunoglobulins Human genes 0.000 description 15
- 108060003951 Immunoglobulins Proteins 0.000 description 15
- 101710041867 PHGDH Proteins 0.000 description 15
- 102100016617 PHGDH Human genes 0.000 description 15
- 230000033115 angiogenesis Effects 0.000 description 15
- 230000002354 daily Effects 0.000 description 15
- 230000001965 increased Effects 0.000 description 15
- 201000000050 myeloid neoplasm Diseases 0.000 description 15
- 238000006467 substitution reaction Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 206010000880 Acute myeloid leukaemia Diseases 0.000 description 14
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N Docetaxel Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 14
- 208000007046 Leukemia, Myeloid, Acute Diseases 0.000 description 14
- 206010025650 Malignant melanoma Diseases 0.000 description 14
- 102000003945 NF-kappa B Human genes 0.000 description 14
- 108010057466 NF-kappa B Proteins 0.000 description 14
- 241000283973 Oryctolagus cuniculus Species 0.000 description 14
- 230000001154 acute Effects 0.000 description 14
- 238000002512 chemotherapy Methods 0.000 description 14
- 230000001684 chronic Effects 0.000 description 14
- 229960003668 docetaxel Drugs 0.000 description 14
- 201000001441 melanoma Diseases 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 238000010798 ubiquitination Methods 0.000 description 14
- 102000004127 Cytokines Human genes 0.000 description 13
- 108090000695 Cytokines Proteins 0.000 description 13
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 13
- RCINICONZNJXQF-MZXODVADSA-N Intaxel Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 13
- 102100018448 RANBP6 Human genes 0.000 description 13
- 101710002562 RANBP6 Proteins 0.000 description 13
- 230000034994 death Effects 0.000 description 13
- 231100000517 death Toxicity 0.000 description 13
- 150000002500 ions Chemical class 0.000 description 13
- 201000003793 myelodysplastic syndrome Diseases 0.000 description 13
- 229920000023 polynucleotide Polymers 0.000 description 13
- 239000002157 polynucleotide Substances 0.000 description 13
- 201000004681 psoriasis Diseases 0.000 description 13
- 230000001105 regulatory Effects 0.000 description 13
- 206010003246 Arthritis Diseases 0.000 description 12
- 108010002350 Interleukin-2 Proteins 0.000 description 12
- 206010026798 Mantle cell lymphomas Diseases 0.000 description 12
- 229960001592 Paclitaxel Drugs 0.000 description 12
- 201000003444 follicular lymphoma Diseases 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- 230000035772 mutation Effects 0.000 description 12
- 238000001356 surgical procedure Methods 0.000 description 12
- 229920001850 Nucleic acid sequence Polymers 0.000 description 11
- 206010039073 Rheumatoid arthritis Diseases 0.000 description 11
- 239000002773 nucleotide Substances 0.000 description 11
- 230000035945 sensitivity Effects 0.000 description 11
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 10
- 208000003950 B-Cell Lymphoma Diseases 0.000 description 10
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 10
- 229960004117 Capecitabine Drugs 0.000 description 10
- 229960004397 Cyclophosphamide Drugs 0.000 description 10
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 10
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 10
- 238000002965 ELISA Methods 0.000 description 10
- 102100008329 FASN Human genes 0.000 description 10
- 101710008102 FASN Proteins 0.000 description 10
- SDUQYLNIPVEERB-QPPQHZFASA-N Gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 10
- 101710010287 YWHAZ Proteins 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 125000000539 amino acid group Chemical group 0.000 description 10
- 238000004166 bioassay Methods 0.000 description 10
- 229960005277 gemcitabine Drugs 0.000 description 10
- 125000003729 nucleotide group Chemical group 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 230000001225 therapeutic Effects 0.000 description 10
- 102100006435 CSF3 Human genes 0.000 description 9
- 229960004562 Carboplatin Drugs 0.000 description 9
- OLESAACUTLOWQZ-UHFFFAOYSA-L Carboplatin Chemical compound O=C1O[Pt]([N]([H])([H])[H])([N]([H])([H])[H])OC(=O)C11CCC1 OLESAACUTLOWQZ-UHFFFAOYSA-L 0.000 description 9
- RZEKVGVHFLEQIL-UHFFFAOYSA-N Celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 9
- 229960003957 Dexamethasone Drugs 0.000 description 9
- 230000035693 Fab Effects 0.000 description 9
- 208000000429 Leukemia, Lymphocytic, Chronic, B-Cell Diseases 0.000 description 9
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 description 9
- 206010040767 Sjogren's syndrome Diseases 0.000 description 9
- 210000003491 Skin Anatomy 0.000 description 9
- 210000001744 T-Lymphocytes Anatomy 0.000 description 9
- 229960000590 celecoxib Drugs 0.000 description 9
- 230000003993 interaction Effects 0.000 description 9
- 230000003211 malignant Effects 0.000 description 9
- 210000000056 organs Anatomy 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 238000001959 radiotherapy Methods 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 229930003347 taxol Natural products 0.000 description 9
- 229960004679 Doxorubicin Drugs 0.000 description 8
- 208000005017 Glioblastoma Diseases 0.000 description 8
- 206010018364 Glomerulonephritis Diseases 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 101700023446 IFNT Proteins 0.000 description 8
- 108090001095 Immunoglobulin G Proteins 0.000 description 8
- 206010037162 Psoriatic arthropathy Diseases 0.000 description 8
- 206010042953 Systemic sclerosis Diseases 0.000 description 8
- 206010047115 Vasculitis Diseases 0.000 description 8
- 230000002159 abnormal effect Effects 0.000 description 8
- 230000000295 complement Effects 0.000 description 8
- 238000003197 gene knockdown Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 230000001613 neoplastic Effects 0.000 description 8
- 239000006186 oral dosage form Substances 0.000 description 8
- 201000001263 psoriatic arthritis Diseases 0.000 description 8
- 230000000306 recurrent Effects 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 8
- 201000009594 systemic scleroderma Diseases 0.000 description 8
- 101710038213 AKR1C4 Proteins 0.000 description 7
- 210000001185 Bone Marrow Anatomy 0.000 description 7
- 101700073818 CDR1 Proteins 0.000 description 7
- 206010008958 Chronic lymphocytic leukaemia Diseases 0.000 description 7
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 7
- 206010061218 Inflammation Diseases 0.000 description 7
- UWKQSNNFCGGAFS-XIFFEERXSA-N Irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 7
- 210000004698 Lymphocytes Anatomy 0.000 description 7
- 206010061289 Metastatic neoplasm Diseases 0.000 description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 7
- 206010028417 Myasthenia gravis Diseases 0.000 description 7
- 108009000071 Non-small cell lung cancer Proteins 0.000 description 7
- 102100009178 RUNX1T1 Human genes 0.000 description 7
- 101710034060 RUNX1T1 Proteins 0.000 description 7
- 229940063683 Taxotere Drugs 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 231100000494 adverse effect Toxicity 0.000 description 7
- 239000011230 binding agent Substances 0.000 description 7
- 239000007884 disintegrant Substances 0.000 description 7
- 239000012530 fluid Substances 0.000 description 7
- 238000009396 hybridization Methods 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 229960004768 irinotecan Drugs 0.000 description 7
- 230000001404 mediated Effects 0.000 description 7
- 230000001394 metastastic Effects 0.000 description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 7
- 239000008108 microcrystalline cellulose Substances 0.000 description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 description 7
- 230000000051 modifying Effects 0.000 description 7
- 238000002703 mutagenesis Methods 0.000 description 7
- 231100000350 mutagenesis Toxicity 0.000 description 7
- MIMNFCVQODTQDP-NDLVEFNKSA-N oblimersen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(S)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 MIMNFCVQODTQDP-NDLVEFNKSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 238000003753 real-time PCR Methods 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 6
- 206010003816 Autoimmune disease Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 6
- 108010050904 Interferons Proteins 0.000 description 6
- 102000014150 Interferons Human genes 0.000 description 6
- 241000229754 Iva xanthiifolia Species 0.000 description 6
- 210000001503 Joints Anatomy 0.000 description 6
- 210000001165 Lymph Nodes Anatomy 0.000 description 6
- 206010060862 Prostate cancer Diseases 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temodal Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 6
- 206010066901 Treatment failure Diseases 0.000 description 6
- 230000003042 antagnostic Effects 0.000 description 6
- 229960000070 antineoplastic Monoclonal antibodies Drugs 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 201000011231 colorectal cancer Diseases 0.000 description 6
- 201000009910 diseases by infectious agent Diseases 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 230000001900 immune effect Effects 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 229960000060 monoclonal antibodies Drugs 0.000 description 6
- 239000006201 parenteral dosage form Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 230000000699 topical Effects 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 description 6
- XGWFJBFNAQHLEF-UHFFFAOYSA-N 9-anthroic acid Chemical compound C1=CC=C2C(C(=O)O)=C(C=CC=C3)C3=CC2=C1 XGWFJBFNAQHLEF-UHFFFAOYSA-N 0.000 description 5
- 108010022043 Antineutrophil Cytoplasmic Antibodies Proteins 0.000 description 5
- 206010059512 Apoptosis Diseases 0.000 description 5
- 101710042422 EPX Proteins 0.000 description 5
- 229960005420 Etoposide Drugs 0.000 description 5
- VJJPUSNTGOMMGY-MRVIYFEKSA-N Etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 5
- 101710025698 FASLG Proteins 0.000 description 5
- 108010064750 Humanized Monoclonal Antibodies Proteins 0.000 description 5
- 102000015434 Humanized Monoclonal Antibodies Human genes 0.000 description 5
- 206010022114 Injury Diseases 0.000 description 5
- 108010047761 Interferon-alpha Proteins 0.000 description 5
- 102000006992 Interferon-alpha Human genes 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 230000036740 Metabolism Effects 0.000 description 5
- 210000004011 Plasma Cells Anatomy 0.000 description 5
- 101700040544 TIMP1 Proteins 0.000 description 5
- 229960001603 Tamoxifen Drugs 0.000 description 5
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 5
- 229940035295 Ting Drugs 0.000 description 5
- UCFGDBYHRUNTLO-QHCPKHFHSA-N Topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 5
- 210000002700 Urine Anatomy 0.000 description 5
- 229960004528 Vincristine Drugs 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 230000001028 anti-proliferant Effects 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 238000001574 biopsy Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 5
- 230000001809 detectable Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 238000001794 hormone therapy Methods 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 230000028709 inflammatory response Effects 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- 230000003902 lesions Effects 0.000 description 5
- 230000004060 metabolic process Effects 0.000 description 5
- 230000035786 metabolism Effects 0.000 description 5
- 230000003000 nontoxic Effects 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000000750 progressive Effects 0.000 description 5
- 238000003757 reverse transcription PCR Methods 0.000 description 5
- 150000003431 steroids Chemical class 0.000 description 5
- 229960000303 topotecan Drugs 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 5
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 206010000830 Acute leukaemia Diseases 0.000 description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
- 210000000988 Bone and Bones Anatomy 0.000 description 4
- 210000004556 Brain Anatomy 0.000 description 4
- 208000003174 Brain Neoplasms Diseases 0.000 description 4
- 210000000481 Breast Anatomy 0.000 description 4
- 229940047495 Celebrex Drugs 0.000 description 4
- 210000001072 Colon Anatomy 0.000 description 4
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 4
- 206010073071 Hepatocellular carcinoma Diseases 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 241000282619 Hylobates lar Species 0.000 description 4
- 229960000310 ISOLEUCINE Drugs 0.000 description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- 229960001375 Lactose Drugs 0.000 description 4
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 4
- 210000000265 Leukocytes Anatomy 0.000 description 4
- 229920002521 Macromolecule Polymers 0.000 description 4
- 210000004379 Membranes Anatomy 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
- 229960005190 Phenylalanine Drugs 0.000 description 4
- 239000008156 Ringer's lactate solution Substances 0.000 description 4
- 206010039491 Sarcoma Diseases 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 229960004799 Tryptophan Drugs 0.000 description 4
- 230000002378 acidificating Effects 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 239000007894 caplet Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000010261 cell growth Effects 0.000 description 4
- 230000001413 cellular Effects 0.000 description 4
- 108091006028 chimera Proteins 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 230000001419 dependent Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000000262 estrogen Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 229960000390 fludarabine Drugs 0.000 description 4
- 210000004602 germ cell Anatomy 0.000 description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 4
- 238000010166 immunofluorescence Methods 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 230000002757 inflammatory Effects 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 150000002605 large molecules Chemical class 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 238000002493 microarray Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000006011 modification reaction Methods 0.000 description 4
- 229960000435 oblimersen Drugs 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 230000036961 partial Effects 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 235000011007 phosphoric acid Nutrition 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- 230000001603 reducing Effects 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 229960004964 temozolomide Drugs 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 239000004474 valine Substances 0.000 description 4
- OMJKFYKNWZZKTK-POHAHGRESA-N (5Z)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide Chemical compound CN(C)N\N=C1/N=CN=C1C(N)=O OMJKFYKNWZZKTK-POHAHGRESA-N 0.000 description 3
- 229940028652 Abraxane Drugs 0.000 description 3
- 206010002023 Amyloidosis Diseases 0.000 description 3
- 206010002022 Amyloidosis Diseases 0.000 description 3
- 206010002224 Anaplastic astrocytoma Diseases 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- 108060006634 CAMP Proteins 0.000 description 3
- 210000001175 Cerebrospinal Fluid Anatomy 0.000 description 3
- 229920001405 Coding region Polymers 0.000 description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N DAUNOMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 3
- 229960000975 Daunorubicin Drugs 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 229940110715 ENZYMES FOR TREATMENT OF WOUNDS AND ULCERS Drugs 0.000 description 3
- 229940088598 Enzyme Drugs 0.000 description 3
- 229940114721 Enzymes FOR DISORDERS OF THE MUSCULO-SKELETAL SYSTEM Drugs 0.000 description 3
- 229940093738 Enzymes for ALIMENTARY TRACT AND METABOLISM Drugs 0.000 description 3
- FRPJXPJMRWBBIH-RBRWEJTLSA-N Estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 3
- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 3
- 229940012356 Eye Drops Drugs 0.000 description 3
- 101700056516 HIF1 Proteins 0.000 description 3
- 101700000053 HIF1A Proteins 0.000 description 3
- 229940022353 Herceptin Drugs 0.000 description 3
- 206010020243 Hodgkin's disease Diseases 0.000 description 3
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 3
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 3
- 210000004969 Inflammatory Cells Anatomy 0.000 description 3
- 210000000936 Intestines Anatomy 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 229960004338 Leuprorelin Drugs 0.000 description 3
- 210000004185 Liver Anatomy 0.000 description 3
- 210000004072 Lung Anatomy 0.000 description 3
- 208000003543 Lymphoma, T-Cell, Cutaneous Diseases 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 206010027406 Mesothelioma Diseases 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Nitrumon Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 3
- 229920000272 Oligonucleotide Polymers 0.000 description 3
- 210000000496 Pancreas Anatomy 0.000 description 3
- 235000019483 Peanut oil Nutrition 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N Prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- 229940082622 Prostaglandin cardiac therapy preparations Drugs 0.000 description 3
- 229940077717 Prostaglandin drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD) Drugs 0.000 description 3
- 210000002307 Prostate Anatomy 0.000 description 3
- 210000001525 Retina Anatomy 0.000 description 3
- 102100000940 SETD2 Human genes 0.000 description 3
- 101700071021 SETD2 Proteins 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 229950006050 Spiromustine Drugs 0.000 description 3
- MLKXDPUZXIRXEP-MFOYZWKCSA-N Sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 3
- 229960000894 Sulindac Drugs 0.000 description 3
- 206010042674 Swelling Diseases 0.000 description 3
- FOCVUCIESVLUNU-UHFFFAOYSA-N ThioTEPA Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 3
- 229960001196 Thiotepa Drugs 0.000 description 3
- 229960003048 Vinblastine Drugs 0.000 description 3
- HOFQVRTUGATRFI-XQKSVPLYSA-N Vinblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 HOFQVRTUGATRFI-XQKSVPLYSA-N 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 208000001756 Virus Disease Diseases 0.000 description 3
- 229940053867 Xeloda Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000002491 angiogenic Effects 0.000 description 3
- 229940019336 antithrombotic Enzymes Drugs 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 230000000903 blocking Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000019522 cellular metabolic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 235000005687 corn oil Nutrition 0.000 description 3
- 239000002285 corn oil Substances 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 235000012343 cottonseed oil Nutrition 0.000 description 3
- 239000002385 cottonseed oil Substances 0.000 description 3
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 3
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 3
- 229960003901 dacarbazine Drugs 0.000 description 3
- 230000003247 decreasing Effects 0.000 description 3
- VPOCYEOOFRNHNL-RQDPQJJXSA-J dexormaplatin Chemical compound Cl[Pt](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N VPOCYEOOFRNHNL-RQDPQJJXSA-J 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000003828 downregulation Effects 0.000 description 3
- 230000002708 enhancing Effects 0.000 description 3
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229940093471 ethyl oleate Drugs 0.000 description 3
- 238000010195 expression analysis Methods 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 230000003176 fibrotic Effects 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000002496 gastric Effects 0.000 description 3
- 201000002406 genetic disease Diseases 0.000 description 3
- 201000011626 grade III astrocytoma Diseases 0.000 description 3
- 229940020899 hematological Enzymes Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 239000008297 liquid dosage form Substances 0.000 description 3
- 230000000527 lymphocytic Effects 0.000 description 3
- 230000005291 magnetic Effects 0.000 description 3
- 201000011614 malignant glioma Diseases 0.000 description 3
- 230000002503 metabolic Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 201000005962 mycosis fungoide Diseases 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- 229940094443 oxytocics Prostaglandins Drugs 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- 230000002093 peripheral Effects 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 229940083249 peripheral vasodilators Enzymes Drugs 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 229960004618 prednisone Drugs 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 230000022983 regulation of cell cycle Effects 0.000 description 3
- 239000008159 sesame oil Substances 0.000 description 3
- 235000011803 sesame oil Nutrition 0.000 description 3
- 231100000486 side effect Toxicity 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000002522 swelling Effects 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 102000003995 transcription factors Human genes 0.000 description 3
- 108090000464 transcription factors Proteins 0.000 description 3
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 3
- 229960002066 vinorelbine Drugs 0.000 description 3
- NFGXHKASABOEEW-UHFFFAOYSA-N (+)-methoprene Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 2
- VPAWVRUHMJVRHU-VGDKGRGNSA-N (2R,4R)-N,N-bis(2-chloroethyl)-4-hydroperoxy-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-amine Chemical compound OO[C@@H]1CCO[P@@](=O)(N(CCCl)CCCl)N1 VPAWVRUHMJVRHU-VGDKGRGNSA-N 0.000 description 2
- SWXOGPJRIDTIRL-HFQRKYADSA-N (4R,7S,10S,13S,16S,19R)-10-(4-aminobutyl)-N-[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2R)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-HFQRKYADSA-N 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8S)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3H-pyrrolo[3,2-e]indole-6-carbonyl]-1H-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- NKUWPVYXJNSCQL-UHFFFAOYSA-L 2,2-bis(aminomethyl)propane-1,3-diol;cyclobutane-1,1-dicarboxylate;platinum(2+) Chemical compound [Pt+2].NCC(CN)(CO)CO.[O-]C(=O)C1(C([O-])=O)CCC1 NKUWPVYXJNSCQL-UHFFFAOYSA-L 0.000 description 2
- QNKJFXARIMSDBR-UHFFFAOYSA-N 3-[2-[bis(2-chloroethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CCN(CCCl)CCCl)C(=O)NC11CCCCC1 QNKJFXARIMSDBR-UHFFFAOYSA-N 0.000 description 2
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 2
- NMUSYJAQQFHJEW-ARQDHWQXSA-N 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3,5-triazin-2-one Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-ARQDHWQXSA-N 0.000 description 2
- MOCVYVBNJQIVOV-TVQRCGJNSA-N 5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-2-methylchromen-4-one Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C)=CC2=O MOCVYVBNJQIVOV-TVQRCGJNSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 229950004955 ADOZELESIN Drugs 0.000 description 2
- VJZITPJGSQKZMX-XDPRQOKASA-N AMRUBICIN Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 2
- 229960004176 Aclarubicin Drugs 0.000 description 2
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 2
- BYRVKDUQDLJUBX-UHFFFAOYSA-N Adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3CC4CC44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-UHFFFAOYSA-N 0.000 description 2
- 229940009456 Adriamycin Drugs 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N Altretamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 2
- 229960001220 Amsacrine Drugs 0.000 description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N Amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 2
- 206010073128 Anaplastic oligodendroglioma Diseases 0.000 description 2
- 208000007502 Anemia Diseases 0.000 description 2
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 2
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 2
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 2
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 2
- 229960001230 Asparagine Drugs 0.000 description 2
- 229960005261 Aspartic Acid Drugs 0.000 description 2
- 208000006673 Asthma Diseases 0.000 description 2
- 108091008154 B cell receptors Proteins 0.000 description 2
- 229950006844 BIZELESIN Drugs 0.000 description 2
- 229940112871 Bisphosphonate drugs affecting bone structure and mineralization Drugs 0.000 description 2
- 206010006002 Bone pain Diseases 0.000 description 2
- 206010006143 Brain stem glioma Diseases 0.000 description 2
- BBZDXMBRAFTCAA-AREMUKBSSA-N CARZELESIN Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 2
- 229960003563 Calcium Carbonate Drugs 0.000 description 2
- 241000282836 Camelus dromedarius Species 0.000 description 2
- 210000001736 Capillaries Anatomy 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229950007509 Carzelesin Drugs 0.000 description 2
- 210000002421 Cell Wall Anatomy 0.000 description 2
- 229920002676 Complementary DNA Polymers 0.000 description 2
- 206010011017 Corneal graft rejection Diseases 0.000 description 2
- 206010011686 Cutaneous vasculitis Diseases 0.000 description 2
- 229960000684 Cytarabine Drugs 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytosar Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N Decitabine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 2
- 229950004203 Droloxifene Drugs 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 108010070635 Edrecolomab Proteins 0.000 description 2
- 229940000733 Emcyt Drugs 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- 229960001842 Estramustine Drugs 0.000 description 2
- WCDWBPCFGJXFJZ-UHFFFAOYSA-N Etanidazole Chemical compound OCCNC(=O)CN1C=CN=C1[N+]([O-])=O WCDWBPCFGJXFJZ-UHFFFAOYSA-N 0.000 description 2
- 229950006566 Etanidazole Drugs 0.000 description 2
- 229950011548 FADROZOLE Drugs 0.000 description 2
- 229950005096 FAZARABINE Drugs 0.000 description 2
- CLPFFLWZZBQMAO-UHFFFAOYSA-N Fadrozole Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 2
- 229960002949 Fluorouracil Drugs 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N Gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 210000001280 Germinal Center Anatomy 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 2
- 229940084910 Gliadel Drugs 0.000 description 2
- 229960002989 Glutamic Acid Drugs 0.000 description 2
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 2
- 210000003128 Head Anatomy 0.000 description 2
- 201000006743 Hodgkin's lymphoma Diseases 0.000 description 2
- 240000006600 Humulus lupulus Species 0.000 description 2
- 235000008694 Humulus lupulus Nutrition 0.000 description 2
- 210000004408 Hybridomas Anatomy 0.000 description 2
- 229950006905 ILMOFOSINE Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N Ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N Imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229940047124 Interferons Drugs 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 102000003814 Interleukin-10 Human genes 0.000 description 2
- 102000003810 Interleukin-18 Human genes 0.000 description 2
- 108090000171 Interleukin-18 Proteins 0.000 description 2
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl myristate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 description 2
- 208000007766 Kaposi Sarcoma Diseases 0.000 description 2
- 206010023332 Keratitis Diseases 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N Lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N Letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- 206010025135 Lupus erythematosus Diseases 0.000 description 2
- 210000004324 Lymphatic System Anatomy 0.000 description 2
- 206010052178 Lymphocytic lymphoma Diseases 0.000 description 2
- 210000003563 Lymphoid Tissue Anatomy 0.000 description 2
- 208000003002 Lymphoma, T-Cell, Peripheral Diseases 0.000 description 2
- 229950002676 MENOGARIL Drugs 0.000 description 2
- 102100015275 MYOM2 Human genes 0.000 description 2
- 101700036747 MYOM2 Proteins 0.000 description 2
- WKPWGQKGSOKKOO-RSFHAFMBSA-N Maitansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 2
- 206010061269 Malignant peritoneal neoplasm Diseases 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 229960003951 Masoprocol Drugs 0.000 description 2
- HCZKYJDFEPMADG-TXEJJXNPSA-N Masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N Melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 206010027191 Meningioma Diseases 0.000 description 2
- LWYJUZBXGAFFLP-OCNCTQISSA-N Menogaril Chemical compound O1[C@@]2(C)[C@H](O)[C@@H](N(C)C)[C@H](O)[C@@H]1OC1=C3C(=O)C(C=C4C[C@@](C)(O)C[C@H](C4=C4O)OC)=C4C(=O)C3=C(O)C=C12 LWYJUZBXGAFFLP-OCNCTQISSA-N 0.000 description 2
- 206010059282 Metastases to central nervous system Diseases 0.000 description 2
- 206010027476 Metastasis Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229960004452 Methionine Drugs 0.000 description 2
- HRHKSTOGXBBQCB-VFWICMBZSA-N Methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 2
- 210000001616 Monocytes Anatomy 0.000 description 2
- 210000000214 Mouth Anatomy 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-Bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- LYPFDBRUNKHDGX-SOGSVHMOSA-N N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 Chemical compound N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 LYPFDBRUNKHDGX-SOGSVHMOSA-N 0.000 description 2
- 108091007229 NSP3 Papain-like protease domain Proteins 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 229960005343 Ondansetron Drugs 0.000 description 2
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 description 2
- 210000003463 Organelles Anatomy 0.000 description 2
- 229950008017 Ormaplatin Drugs 0.000 description 2
- 210000002997 Osteoclasts Anatomy 0.000 description 2
- 241000237988 Patellidae Species 0.000 description 2
- 229950009351 Perfosfamide Drugs 0.000 description 2
- 229920001451 Polypropylene glycol Polymers 0.000 description 2
- 229950004406 Porfiromycin Drugs 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N Procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960002429 Proline Drugs 0.000 description 2
- BBNQQADTFFCFGB-UHFFFAOYSA-N Purpurin Natural products C1=CC=C2C(=O)C3=C(O)C(O)=CC(O)=C3C(=O)C2=C1 BBNQQADTFFCFGB-UHFFFAOYSA-N 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 206010037844 Rash Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 210000000664 Rectum Anatomy 0.000 description 2
- 208000006265 Renal Cell Carcinoma Diseases 0.000 description 2
- 206010038934 Retinopathy proliferative Diseases 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 108010001645 Rituximab Proteins 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 102000005632 Single-Chain Antibodies Human genes 0.000 description 2
- 108010070144 Single-Chain Antibodies Proteins 0.000 description 2
- 108020004459 Small Interfering RNA Proteins 0.000 description 2
- 229940032147 Starch Drugs 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 210000002784 Stomach Anatomy 0.000 description 2
- 210000002536 Stromal Cells Anatomy 0.000 description 2
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 2
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 229940061353 Temodar Drugs 0.000 description 2
- 229960001278 Teniposide Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 229950002376 Tirapazamine Drugs 0.000 description 2
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 2
- 229960001727 Tretinoin Drugs 0.000 description 2
- SHGAZHPCJJPHSC-NWVFGJFESA-N Tretinoin Chemical compound OC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NWVFGJFESA-N 0.000 description 2
- GCPXMJHSNVMWNM-UHFFFAOYSA-N Trihydroxyarsenite(Iii) Chemical compound O[As](O)O GCPXMJHSNVMWNM-UHFFFAOYSA-N 0.000 description 2
- 229960004824 Triptorelin Drugs 0.000 description 2
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 2
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 2
- 206010068760 Ulcers Diseases 0.000 description 2
- 230000036462 Unbound Effects 0.000 description 2
- 210000004291 Uterus Anatomy 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 102100015249 VEGFA Human genes 0.000 description 2
- 101700055524 VME1 Proteins 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N Vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 2
- 229960004355 Vindesine Drugs 0.000 description 2
- XLMPPFTZALNBFS-INIZCTEOSA-N Vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 2
- 229950003017 Zeniplatin Drugs 0.000 description 2
- XRASPMIURGNCCH-UHFFFAOYSA-N Zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 2
- ODEDPKNSRBCSDO-UHFFFAOYSA-N [2-(hexadecylsulfanylmethyl)-3-methoxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCSCC(COC)COP([O-])(=O)OCC[N+](C)(C)C ODEDPKNSRBCSDO-UHFFFAOYSA-N 0.000 description 2
- LIQODXNTTZAGID-OCBXBXKTSA-N [4-[(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-8-oxo-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-9-yl]-2,6-dimethoxyphenyl] dihydrogen phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000000240 adjuvant Effects 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 230000000172 allergic Effects 0.000 description 2
- 201000005794 allergic hypersensitivity disease Diseases 0.000 description 2
- 229960000473 altretamine Drugs 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229960002550 amrubicin Drugs 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000003110 anti-inflammatory Effects 0.000 description 2
- 230000000259 anti-tumor Effects 0.000 description 2
- 230000000890 antigenic Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000008135 aqueous vehicle Substances 0.000 description 2
- 229960002594 arsenic trioxide Drugs 0.000 description 2
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 2
- 230000002917 arthritic Effects 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 201000009596 autoimmune hypersensitivity disease Diseases 0.000 description 2
- 230000001580 bacterial Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 229960002903 benzyl benzoate Drugs 0.000 description 2
- 230000003115 biocidal Effects 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000004271 bone marrow stromal cells Anatomy 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000000973 chemotherapeutic Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 201000010989 colorectal carcinoma Diseases 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 101700013060 cul-4 Proteins 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 229960003603 decitabine Drugs 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000004059 degradation Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229950002389 diaziquone Drugs 0.000 description 2
- 150000002019 disulfides Chemical class 0.000 description 2
- 229960001776 edrecolomab Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000029578 entry into host Effects 0.000 description 2
- 229960004750 estramustine phosphate Drugs 0.000 description 2
- WVYXNIXAMZOZFK-UHFFFAOYSA-N ethyl N-[2,5-bis(aziridin-1-yl)-4-(ethoxycarbonylamino)-3,6-dioxocyclohexa-1,4-dien-1-yl]carbamate Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 2
- 229960000752 etoposide phosphate Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229950003662 fenretinide Drugs 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 2
- 235000008191 folinic acid Nutrition 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- 230000003325 follicular Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000004153 glucose metabolism Effects 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 150000004676 glycans Polymers 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 230000034659 glycolysis Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000003394 haemopoietic Effects 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- 108060003552 hemocyanin family Proteins 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 230000001976 improved Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 229940079866 intestinal antibiotics Drugs 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229940074928 isopropyl myristate Drugs 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 229960003881 letrozole Drugs 0.000 description 2
- 229960001691 leucovorin Drugs 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 201000005244 lung non-small cell carcinoma Diseases 0.000 description 2
- 230000002101 lytic Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 101700045377 mvp1 Proteins 0.000 description 2
- 201000003142 neovascular glaucoma Diseases 0.000 description 2
- 201000011519 neuroendocrine tumor Diseases 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 239000002687 nonaqueous vehicle Substances 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 2
- 230000002148 osteoclast Effects 0.000 description 2
- 201000005163 papillary serous adenocarcinoma Diseases 0.000 description 2
- 229960001744 pegaspargase Drugs 0.000 description 2
- 108010001564 pegaspargase Proteins 0.000 description 2
- 201000007923 peripheral T-cell lymphoma Diseases 0.000 description 2
- 201000002524 peritoneal carcinoma Diseases 0.000 description 2
- 238000002823 phage display Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000000865 phosphorylative Effects 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000010837 poor prognosis Methods 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002335 preservative Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 201000006037 primary mediastinal B-cell lymphoma Diseases 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 239000003881 protein kinase c inhibitor Substances 0.000 description 2
- 230000001185 psoriatic Effects 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 201000000306 sarcoidosis Diseases 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000008354 sodium chloride injection Substances 0.000 description 2
- 230000000392 somatic Effects 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical class CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 230000004936 stimulating Effects 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 230000002195 synergetic Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 2
- 229960002197 temoporfin Drugs 0.000 description 2
- 230000036962 time dependent Effects 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- ORYDPOVDJJZGHQ-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=CC2=[N+]([O-])C(N)=N[N+]([O-])=C21 ORYDPOVDJJZGHQ-UHFFFAOYSA-N 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 238000003325 tomography Methods 0.000 description 2
- 231100000440 toxicity profile Toxicity 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 2
- 230000004565 tumor cell growth Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 229960002730 vapreotide Drugs 0.000 description 2
- 229960003862 vemurafenib Drugs 0.000 description 2
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 2
- 229960001771 vorozole Drugs 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 239000008136 water-miscible vehicle Substances 0.000 description 2
- 229960004276 zoledronic acid Drugs 0.000 description 2
- NDTYTMIUWGWIMO-SNVBAGLBSA-N (-)-isocarveol Chemical compound CC(=C)[C@H]1CCC(CO)=CC1 NDTYTMIUWGWIMO-SNVBAGLBSA-N 0.000 description 1
- 229930007631 (-)-perillyl alcohol Natural products 0.000 description 1
- OPFTUNCRGUEPRZ-QLFBSQMISA-N (-)-β-elemene Chemical compound CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 description 1
- ZROHGHOFXNOHSO-BNTLRKBRSA-L (1R,2R)-cyclohexane-1,2-diamine;oxalate;platinum(2+) Chemical compound [H][N]([C@@H]1CCCC[C@H]1[N]1([H])[H])([H])[Pt]11OC(=O)C(=O)O1 ZROHGHOFXNOHSO-BNTLRKBRSA-L 0.000 description 1
- BLOFGONIVNXZME-YDMGZANHSA-N (1R,2R,3R,4S,5R)-4-amino-5-methylsulfanylcyclopentane-1,2,3-triol Chemical compound CS[C@@H]1[C@@H](N)[C@@H](O)[C@@H](O)[C@H]1O BLOFGONIVNXZME-YDMGZANHSA-N 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N (1R,3S,5Z)-5-{2-[(1R,3aS,4E,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-octahydro-1H-inden-4-ylidene]ethylidene}-4-methylidenecyclohexane-1,3-diol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- YADVRLOQIWILGX-MIWLTHJTSA-N (1S,2Z,4E,8E,12E)-5,9,13-trimethyl-2-propan-2-ylcyclotetradeca-2,4,8,12-tetraen-1-ol Chemical compound CC(C)C/1=C/C=C(C)/CC\C=C(C)\CC\C=C(C)\C[C@@H]\1O YADVRLOQIWILGX-MIWLTHJTSA-N 0.000 description 1
- FXPSZLHFJDHOMI-DHZHZOJOSA-N (2E)-4-methoxy-3-methylsulfanyl-2-(nitrosomethylidene)-6-pyridin-2-yl-1H-pyridine Chemical compound COC1=C(SC)\C(=C/N=O)NC(C=2N=CC=CC=2)=C1 FXPSZLHFJDHOMI-DHZHZOJOSA-N 0.000 description 1
- BUSGWUFLNHIBPT-XYBORKQMSA-N (2E,4E,6E)-7-[(1R,5R,6S)-3-[[(2E,4E)-5-cyclohexylpenta-2,4-dienoyl]amino]-5-hydroxy-2-oxo-7-oxabicyclo[4.1.0]hept-3-en-5-yl]hepta-2,4,6-trienoic acid Chemical compound C([C@]([C@H]1O[C@H]1C1=O)(O)/C=C/C=C/C=C/C(=O)O)=C1NC(=O)\C=C\C=C\C1CCCCC1 BUSGWUFLNHIBPT-XYBORKQMSA-N 0.000 description 1
- LCADVYTXPLBAGB-AUQKUMLUSA-N (2E,4E,6Z,8E,10E,14E)-13-hydroxy-N-(1-hydroxypropan-2-yl)-2,10,12,14,16-pentamethyl-18-phenyloctadeca-2,4,6,8,10,14-hexaenamide Chemical compound OCC(C)NC(=O)C(\C)=C\C=C\C=C/C=C/C(/C)=C/C(C)C(O)C(\C)=C\C(C)CCC1=CC=CC=C1 LCADVYTXPLBAGB-AUQKUMLUSA-N 0.000 description 1
- NOENHWMKHNSHGX-FAZSUBJTSA-N (2R)-1-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-(ca Chemical compound C([C@@H](C(=O)N[C@H](CCCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@H](CCC1)C(=O)NC(C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 NOENHWMKHNSHGX-FAZSUBJTSA-N 0.000 description 1
- FKHUGQZRBPETJR-RXSRXONKSA-N (2R)-2-[[(4R)-4-[[(2S)-2-[[(2R)-2-[(3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxypropanoyl]amino]propanoyl]amino]-5-amino-5-oxopentanoyl]amino]-6-(octadecanoylamino)hexanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@H](C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@@H]1NC(C)=O FKHUGQZRBPETJR-RXSRXONKSA-N 0.000 description 1
- RXWNCPJZOCPEPQ-FNQTVZJVSA-N (2R)-2-amino-N-[(2S,3S,4R,5R)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]-3-(4-methoxyphenyl)propanamide Chemical compound C1=CC(OC)=CC=C1C[C@@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-FNQTVZJVSA-N 0.000 description 1
- SWTGJCNCBUCXSS-ISUZDFFFSA-N (2R)-3,4-dihydroxy-2-[(4S)-2-phenyl-1,3-dioxolan-4-yl]-2H-furan-5-one Chemical compound OC1=C(O)C(=O)O[C@@H]1[C@H]1OC(C=2C=CC=CC=2)OC1 SWTGJCNCBUCXSS-ISUZDFFFSA-N 0.000 description 1
- RCGXNDQKCXNWLO-YUHQQKLOSA-N (2R)-N-[(2S)-5-amino-1-[[(2R,3S)-1-[[(3S,6Z,9S,12R,15R,18R,19R)-9-benzyl-15-[(2S)-butan-2-yl]-6-ethylidene-19-methyl-2,5,8,11,14,17-hexaoxo-3,12-di(propan-2-yl)-1-oxa-4,7,10,13,16-pentazacyclononadec-18-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxopent Chemical compound N([C@@H](CCCN)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]1C(N[C@@H](C(=O)N[C@@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)NC(/C(=O)N[C@H](C(=O)O[C@@H]1C)C(C)C)=C\C)C(C)C)[C@@H](C)CC)=O)C(=O)[C@H]1CCCN1C(=O)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](NC(=O)CCCC(C)C)C(C)C)[C@@H](C)O)C(C)C)C(C)C RCGXNDQKCXNWLO-YUHQQKLOSA-N 0.000 description 1
- PAYBYKKERMGTSS-MNCSTQPFSA-N (2R,3R,3aS,9aR)-7-fluoro-2-(hydroxymethyl)-6-imino-2,3,3a,9a-tetrahydrofuro[1,2][1,3]oxazolo[3,4-a]pyrimidin-3-ol Chemical compound N=C1C(F)=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 PAYBYKKERMGTSS-MNCSTQPFSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2R,3R,4S,5R,6R)-4-[(2S,3R,4S,5R,6R)-3,5-dihydroxy-4-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- GJNXBNATEDXMAK-PFLSVRRQSA-N (2S)-1-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-[bi Chemical compound C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 GJNXBNATEDXMAK-PFLSVRRQSA-N 0.000 description 1
- ZZKNRXZVGOYGJT-VKHMYHEASA-N (2S)-2-[(2-phosphonoacetyl)amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)CP(O)(O)=O ZZKNRXZVGOYGJT-VKHMYHEASA-N 0.000 description 1
- XDZGQQRZJDKPTG-HBNQUELISA-N (2S)-2-[(3S,6S)-6-[2-[(1R,2R,4aS,8aS)-1-hydroxy-2,4a,5,5,8a-pentamethyl-2,3,4,6,7,8-hexahydronaphthalen-1-yl]ethyl]-6-methyldioxan-3-yl]propanoic acid Chemical compound O1O[C@H]([C@H](C)C(O)=O)CC[C@@]1(C)CC[C@]1(O)[C@@]2(C)CCCC(C)(C)[C@]2(C)CC[C@H]1C XDZGQQRZJDKPTG-HBNQUELISA-N 0.000 description 1
- XVOCEQLNJQGCQG-ACRSGXKRSA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl- Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C=CC=CC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 XVOCEQLNJQGCQG-ACRSGXKRSA-N 0.000 description 1
- CUCSSYAUKKIDJV-FAXBSAIASA-N (2S)-2-[[(2R)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]-methylamino]-3-phenylpropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-4-methylpent Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)N(C)C(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CUCSSYAUKKIDJV-FAXBSAIASA-N 0.000 description 1
- MJINRRBEMOLJAK-DCAQKATOSA-N (2S)-2-[[(2S)-6-amino-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCN=C(N)N MJINRRBEMOLJAK-DCAQKATOSA-N 0.000 description 1
- VGGGPCQERPFHOB-RDBSUJKOSA-N (2S)-2-[[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]amino]-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-RDBSUJKOSA-N 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N (2S)-2-[[4-[1-(2,4-diaminopteridin-6-yl)butan-2-yl]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- ZUQBAQVRAURMCL-DOMZBBRYSA-N (2S)-2-[[4-[2-[(6R)-2-amino-4-oxo-5,6,7,8-tetrahydro-1H-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioic acid Chemical compound C([C@@H]1CC=2C(=O)N=C(NC=2NC1)N)CC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZUQBAQVRAURMCL-DOMZBBRYSA-N 0.000 description 1
- JRBXPUUAYKCCLQ-QMMMGPOBSA-N (2S)-2-amino-2-[3-hydroxy-4-(hydroxymethyl)phenyl]acetic acid Chemical compound OC(=O)[C@@H](N)C1=CC=C(CO)C(O)=C1 JRBXPUUAYKCCLQ-QMMMGPOBSA-N 0.000 description 1
- YOZSEGPJAXTSFZ-ZETCQYMHSA-N (2S)-2-amino-3-(5-hydroxypyridin-2-yl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=N1 YOZSEGPJAXTSFZ-ZETCQYMHSA-N 0.000 description 1
- RPEPXOHTYVXVMA-CIUDSAMLSA-N (2S)-2-amino-5-[[(2S)-1-[[(1S)-1-carboxy-4-(3H-diazirin-3-yl)-4-oxobutyl]amino]-5-(3H-diazirin-3-yl)-1,5-dioxopentan-2-yl]amino]-5-oxopentanoic acid Chemical compound C([C@H](NC(=O)CC[C@H](N)C(O)=O)C(=O)N[C@@H](CCC(=O)C1N=N1)C(O)=O)CC(=O)C1N=N1 RPEPXOHTYVXVMA-CIUDSAMLSA-N 0.000 description 1
- UUSZLLQJYRSZIS-GHRWIAHFSA-N (2S)-N-[(2R)-1-[[(3S,6R,8S,12S,13R,16R,17S,23S)-13-[(2S)-butan-2-yl]-12-hydroxy-20-[(4-methoxyphenyl)methyl]-6,17,21-trimethyl-3-(2-methylpropyl)-2,5,7,10,15,19,22-heptaoxo-8-propan-2-yl-9,18-dioxa-1,4,14,21-tetrazabicyclo[21.3.0]hexacosan-16-yl]amino]-4- Chemical compound CN([C@H](CC(C)C)C(=O)N[C@H]1C(=O)N[C@@H]([C@H](CC(=O)O[C@H](C(=O)[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N(C)C(CC=2C=CC(OC)=CC=2)C(=O)O[C@H]1C)C(C)C)O)[C@@H](C)CC)C(=O)[C@@H]1CCCN1C(=O)C(C)=O UUSZLLQJYRSZIS-GHRWIAHFSA-N 0.000 description 1
- RWHUEXWOYVBUCI-ITQXDASVSA-N (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-3-( Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 description 1
- GJKXGJCSJWBJEZ-XRSSZCMZSA-N (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 GJKXGJCSJWBJEZ-XRSSZCMZSA-N 0.000 description 1
- CFCUWKMKBJTWLW-BGLFSJPPSA-N (2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5R,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5S,6R)-4-[(2S,4R,5S,6R)-4,5-dih Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BGLFSJPPSA-N 0.000 description 1
- BEHHCQFBLOARIX-APTPAJQOSA-N (2S,3S)-2-aminooctadecane-1,3-diol;hydrochloride Chemical compound Cl.CCCCCCCCCCCCCCC[C@H](O)[C@@H](N)CO BEHHCQFBLOARIX-APTPAJQOSA-N 0.000 description 1
- HWMMBHOXHRVLCU-QOUANJGESA-N (2S,4S,5S)-4-[(1E,3E,5E)-7-[(2R,6R)-6-[(2R,3S,4aR,12bS)-2,3,4a,8,12b-pentahydroxy-3-methyl-1,7,12-trioxo-2,4-dihydrobenzo[a]anthracen-9-yl]-2-methyloxan-3-yl]oxy-7-oxohepta-1,3,5-trienyl]-2,5-dimethyl-1,3-dioxolane-2-carboxylic acid Chemical compound C[C@@H]1O[C@](C)(C(O)=O)O[C@H]1\C=C\C=C\C=C\C(=O)OC1[C@@H](C)O[C@@H](C=2C(=C3C(=O)C4=C([C@]5(C(=O)[C@H](O)[C@@](C)(O)C[C@@]5(O)C=C4)O)C(=O)C3=CC=2)O)CC1 HWMMBHOXHRVLCU-QOUANJGESA-N 0.000 description 1
- JSUANXYBLFQZGI-HDFWGNLJSA-N (2Z,4S,5R)-N-[4-[(2,3-dihydroxybenzoyl)amino]butyl]-N-[3-[(2,3-dihydroxybenzoyl)amino]propyl]-5-methyl-2-(6-oxocyclohexa-2,4-dien-1-ylidene)-1,3-oxazolidine-4-carboxamide Chemical compound O=C([C@H]1NC(/O[C@@H]1C)=C\1C(C=CC=C/1)=O)N(CCCNC(=O)C=1C(=C(O)C=CC=1)O)CCCCNC(=O)C1=CC=CC(O)=C1O JSUANXYBLFQZGI-HDFWGNLJSA-N 0.000 description 1
- AAWZDTNXLSGCEK-VNDMDPINSA-N (3R)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound OC1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-VNDMDPINSA-N 0.000 description 1
- UYRMXZIBPZVBNO-QPJJXVBHSA-N (4E)-4-[amino-(hydroxyamino)methylidene]-2-hydroxycyclohexa-2,5-dien-1-one Chemical compound ONC(/N)=C1\C=CC(=O)C(O)=C1 UYRMXZIBPZVBNO-QPJJXVBHSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-19-[[(2R)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-N-[(2R,3R)-1,3-dihydroxybutan-2-yl]-7-[(1R)-1-hydroxyethyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- DRCNRVYVCHHIJP-AQBORDMYSA-N (4S)-4-[[(2S)-6-amino-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]-5-[[(2S)-1-[[(1S)-1-carboxy-2-(4-hydroxyphenyl)ethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DRCNRVYVCHHIJP-AQBORDMYSA-N 0.000 description 1
- DLWOTOMWYCRPLK-UVTDQMKNSA-N (4Z)-5-amino-6-(7-amino-6-methoxy-5,8-dioxoquinolin-2-yl)-4-(4,5-dimethoxy-6-oxocyclohexa-2,4-dien-1-ylidene)-3-methyl-1H-pyridine-2-carboxylic acid Chemical compound C1=CC(OC)=C(OC)C(=O)\C1=C\1C(N)=C(C=2N=C3C(=O)C(N)=C(OC)C(=O)C3=CC=2)NC(C(O)=O)=C/1C DLWOTOMWYCRPLK-UVTDQMKNSA-N 0.000 description 1
- GTEXXGIEZVKSLH-YPMHNXCESA-N (4aS,12bR)-8,10-dihydroxy-2,5,5,9-tetramethyl-3,4,4a,12b-tetrahydronaphtho[2,3-c]isochromene-7,12-dione Chemical compound O=C1C2=CC(O)=C(C)C(O)=C2C(=O)C2=C1[C@@H]1C=C(C)CC[C@@H]1C(C)(C)O2 GTEXXGIEZVKSLH-YPMHNXCESA-N 0.000 description 1
- HLAKJNQXUARACO-ZDUSSCGKSA-N (5'R)-5'-hydroxy-2',5',7'-trimethylspiro[cyclopropane-1,6'-indene]-4'-one Chemical compound O=C([C@@]1(O)C)C2=CC(C)=CC2=C(C)C21CC2 HLAKJNQXUARACO-ZDUSSCGKSA-N 0.000 description 1
- WTSKMKRYHATLLL-UHFFFAOYSA-N (6-benzoyloxy-3-cyanopyridin-2-yl) 3-[3-(ethoxymethyl)-5-fluoro-2,6-dioxopyrimidine-1-carbonyl]benzoate Chemical compound O=C1N(COCC)C=C(F)C(=O)N1C(=O)C1=CC=CC(C(=O)OC=2C(=CC=C(OC(=O)C=3C=CC=CC=3)N=2)C#N)=C1 WTSKMKRYHATLLL-UHFFFAOYSA-N 0.000 description 1
- LKBBOPGQDRPCDS-YAOXHJNESA-N (7S,9R,10R)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-9-ethyl-4,6,9,10,11-pentahydroxy-8,10-dihydro-7H-tetracene-5,12-dione Chemical compound O([C@H]1C[C@]([C@@H](C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)O)(O)CC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 LKBBOPGQDRPCDS-YAOXHJNESA-N 0.000 description 1
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7S,9S)-7-[(2R,4S,5R,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 1
- PTBPQBZWBIRISO-IAGVQPJWSA-N (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-[(E)-N-[(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-ylidene)amino]-C-methylcarbonimidoyl]-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\N=C1CC(C)(C)N(O)C(C)(C)C1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 PTBPQBZWBIRISO-IAGVQPJWSA-N 0.000 description 1
- KMSKQZKKOZQFFG-YXRRJAAWSA-N (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-6-methyl-5-[(2R)-oxan-2-yl]oxyoxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@@H]1CCCCO1 KMSKQZKKOZQFFG-YXRRJAAWSA-N 0.000 description 1
- JVHPTYWUBOQMBP-RVFAQHLVSA-N (7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride Chemical compound Cl.C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 JVHPTYWUBOQMBP-RVFAQHLVSA-N 0.000 description 1
- VHZXNQKVFDBFIK-NBBHSKLNSA-N (8R,9S,10R,13S,14S,16R)-16-fluoro-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)(C([C@H](F)C4)=O)[C@@H]4[C@@H]3CC=C21 VHZXNQKVFDBFIK-NBBHSKLNSA-N 0.000 description 1
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8S,11R,13R,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 1
- VAPSMQAHNAZRKC-PQWRYPMOSA-N (8S,9S,10R,13S,14S,17S)-17-(tert-butylcarbamoyl)-10,13-dimethyl-2,7,8,9,11,12,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthrene-3-carboxylic acid Chemical compound C1C=C2C=C(C(O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)NC(C)(C)C)[C@@]1(C)CC2 VAPSMQAHNAZRKC-PQWRYPMOSA-N 0.000 description 1
- 239000001124 (E)-prop-1-ene-1,2,3-tricarboxylic acid Substances 0.000 description 1
- OJRZEKJECRTBPJ-NGAMADIESA-N (Z,5S)-5-acetamido-1-diazonio-6-hydroxy-6-oxohex-1-en-2-olate Chemical compound CC(=O)N[C@H](C(O)=O)CC\C([O-])=C\[N+]#N OJRZEKJECRTBPJ-NGAMADIESA-N 0.000 description 1
- NBEALWAVEGMZQY-UHFFFAOYSA-N 1,1-diphenylprop-2-ynyl N-cyclohexylcarbamate Chemical compound C=1C=CC=CC=1C(C#C)(C=1C=CC=CC=1)OC(=O)NC1CCCCC1 NBEALWAVEGMZQY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- OUPZKGBUJRBPGC-HLTSFMKQSA-N 1,5-bis[[(2R)-oxiran-2-yl]methyl]-3-[[(2S)-oxiran-2-yl]methyl]-1,3,5-triazinane-2,4,6-trione Chemical compound O=C1N(C[C@H]2OC2)C(=O)N(C[C@H]2OC2)C(=O)N1C[C@H]1CO1 OUPZKGBUJRBPGC-HLTSFMKQSA-N 0.000 description 1
- UOAFGUOASVSLPK-UHFFFAOYSA-N 1-(2-chloroethyl)-3-(2,2-dimethylpropyl)-1-nitrosourea Chemical compound CC(C)(C)CNC(=O)N(N=O)CCCl UOAFGUOASVSLPK-UHFFFAOYSA-N 0.000 description 1
- YQYBWJPESSJLTK-HXFLIBJXSA-N 1-(2-chloroethyl)-3-[(2R,3S,4R,6S)-3-hydroxy-2-(hydroxymethyl)-6-methoxyoxan-4-yl]-1-nitrosourea Chemical compound CO[C@@H]1C[C@@H](NC(=O)N(CCCl)N=O)[C@H](O)[C@@H](CO)O1 YQYBWJPESSJLTK-HXFLIBJXSA-N 0.000 description 1
- RCLLNBVPCJDIPX-UHFFFAOYSA-N 1-(2-chloroethyl)-3-[2-(dimethylsulfamoyl)ethyl]-1-nitrosourea Chemical compound CN(C)S(=O)(=O)CCNC(=O)N(N=O)CCCl RCLLNBVPCJDIPX-UHFFFAOYSA-N 0.000 description 1
- QRCYUEWGGBWKRL-UHFFFAOYSA-N 1-(3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione Chemical class C1C2=CC=CC=C2C(=O)N1N1C(=O)CCCC1=O QRCYUEWGGBWKRL-UHFFFAOYSA-N 0.000 description 1
- JQJSFAJISYZPER-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(2,3-dihydro-1H-inden-5-ylsulfonyl)urea Chemical compound C1=CC(Cl)=CC=C1NC(=O)NS(=O)(=O)C1=CC=C(CCC2)C2=C1 JQJSFAJISYZPER-UHFFFAOYSA-N 0.000 description 1
- NSMXQKNUPPXBRG-UHFFFAOYSA-N 1-(5-hydroxyhexyl)-3,7-dimethylpurine-2,6-dione Chemical compound O=C1N(CCCCC(O)C)C(=O)N(C)C2=C1N(C)C=N2 NSMXQKNUPPXBRG-UHFFFAOYSA-N 0.000 description 1
- SNYUHPPZINRDSG-UHFFFAOYSA-N 1-(oxiran-2-ylmethyl)-4-[1-(oxiran-2-ylmethyl)piperidin-4-yl]piperidine Chemical compound C1CC(C2CCN(CC3OC3)CC2)CCN1CC1CO1 SNYUHPPZINRDSG-UHFFFAOYSA-N 0.000 description 1
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 1
- 108040005185 1-phosphatidylinositol-3-kinase activity proteins Proteins 0.000 description 1
- NJWBUDCAWGTQAS-UHFFFAOYSA-N 2-(chrysen-6-ylmethylamino)-2-methylpropane-1,3-diol;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1=CC=C2C(CNC(CO)(CO)C)=CC3=C(C=CC=C4)C4=CC=C3C2=C1 NJWBUDCAWGTQAS-UHFFFAOYSA-N 0.000 description 1
- ARUGKOZUKWAXDS-SEWALLKFSA-N 2-[(2E)-2-[(3aS,4S,5R,6aS)-5-hydroxy-4-[(3S,4S)-3-hydroxy-4-methylnona-1,6-diynyl]-3,3a,4,5,6,6a-hexahydro-1H-pentalen-2-ylidene]ethoxy]acetic acid Chemical compound C1\C(=C/COCC(O)=O)C[C@@H]2[C@@H](C#C[C@@H](O)[C@@H](C)CC#CCC)[C@H](O)C[C@@H]21 ARUGKOZUKWAXDS-SEWALLKFSA-N 0.000 description 1
- JUNILAWHCDMYAE-HGJPKUQDSA-N 2-[(3E,7E,9E,17E)-14,19-dihydroxy-3,5,9,11,13,15,17-heptamethyl-12-oxononadeca-3,7,9,17-tetraenyl]-2,3-dihydropyran-6-one Chemical compound OC/C=C(C)/CC(C)C(O)C(C)C(=O)C(C)/C=C(\C)/C=C/CC(C)\C=C(/C)CCC1CC=CC(=O)O1 JUNILAWHCDMYAE-HGJPKUQDSA-N 0.000 description 1
- KPRFMAZESAKTEJ-UHFFFAOYSA-N 2-[1-amino-4-[2,5-dioxo-4-(1-phenylethyl)pyrrolidin-3-yl]-1-oxobutan-2-yl]-5-carbamoylheptanedioic acid;azane Chemical compound [NH4+].[NH4+].C=1C=CC=CC=1C(C)C1C(CCC(C(CCC(CC([O-])=O)C(N)=O)C([O-])=O)C(N)=O)C(=O)NC1=O KPRFMAZESAKTEJ-UHFFFAOYSA-N 0.000 description 1
- MHXVDXXARZCVRK-WCWDXBQESA-N 2-[2-[4-[(E)-3,3,3-trifluoro-1,2-diphenylprop-1-enyl]phenoxy]ethylamino]ethanol Chemical compound C1=CC(OCCNCCO)=CC=C1C(\C=1C=CC=CC=1)=C(C(F)(F)F)/C1=CC=CC=C1 MHXVDXXARZCVRK-WCWDXBQESA-N 0.000 description 1
- PXJJOGITBQXZEQ-JTHROIFXSA-M 2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]ethyl-trimethylazanium;iodide Chemical compound [I-].C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCC[N+](C)(C)C)=CC=1)/C1=CC=CC=C1 PXJJOGITBQXZEQ-JTHROIFXSA-M 0.000 description 1
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N 2-[[2-[bis(2-hydroxyethyl)amino]-4-piperidin-1-ylpyrimido[5,4-d]pyrimidin-6-yl]-(2-hydroxyethyl)amino]ethanol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- JRYMOPZHXMVHTA-DAGMQNCNSA-N 2-amino-7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1H-pyrrolo[2,3-d]pyrimidin-4-one Chemical compound C1=CC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O JRYMOPZHXMVHTA-DAGMQNCNSA-N 0.000 description 1
- VDCRFBBZFHHYGT-IOSLPCCCSA-N 2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-enyl-3H-purine-6,8-dione Chemical compound O=C1N(CC=C)C=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VDCRFBBZFHHYGT-IOSLPCCCSA-N 0.000 description 1
- HVXBOLULGPECHP-WAYWQWQTSA-N 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
- DSWLRNLRVBAVFC-UHFFFAOYSA-N 2-methylsulfinyl-1-pyridin-2-ylethanone Chemical compound CS(=O)CC(=O)C1=CC=CC=N1 DSWLRNLRVBAVFC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- GRLUHXSUZYFZCW-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-N,N-dimethylpropan-1-amine;dihydrochloride Chemical compound Cl.Cl.C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 GRLUHXSUZYFZCW-UHFFFAOYSA-N 0.000 description 1
- GTJXPMSTODOYNP-BTKVJIOYSA-N 3-[(E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 GTJXPMSTODOYNP-BTKVJIOYSA-N 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- WELIVEBWRWAGOM-UHFFFAOYSA-N 3-amino-N-[2-[2-(3-aminopropanoylamino)ethyldisulfanyl]ethyl]propanamide Chemical compound NCCC(=O)NCCSSCCNC(=O)CCN WELIVEBWRWAGOM-UHFFFAOYSA-N 0.000 description 1
- XSCKKKKCZBNKQZ-UHFFFAOYSA-N 3-chloroquinoxaline-2-sulfonamide Chemical compound C1=CC=C2N=C(Cl)C(S(=O)(=O)N)=NC2=C1 XSCKKKKCZBNKQZ-UHFFFAOYSA-N 0.000 description 1
- HXZRMADPDYFMEB-MLTUFRGDSA-N 3-hydroxy-N-[3-[8-[(E)-6-hydroxy-3,5-dimethylhept-4-enyl]-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]propyl]-2-methyl-4-[[2-[3-methyl-6-[(Z)-2-oxopent-3-enyl]oxan-2-yl]acetyl]amino]butanamide Chemical compound O1C(CC(=O)\C=C/C)CCC(C)C1CC(=O)NCC(O)C(C)C(=O)NCCCC1C(C)CCC2(OC(CCC(C)\C=C(/C)C(C)O)CCC2)O1 HXZRMADPDYFMEB-MLTUFRGDSA-N 0.000 description 1
- PDQGEKGUTOTUNV-TZSSRYMLSA-N 4'-deoxy-4'-iododoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](I)[C@H](C)O1 PDQGEKGUTOTUNV-TZSSRYMLSA-N 0.000 description 1
- LIETVYHJBSLSSW-UHFFFAOYSA-N 4,6,9-trihydroxy-8-methyl-3,4-dihydro-2H-anthracen-1-one Chemical compound OC1CCC(=O)C2=C1C=C1C=C(O)C=C(C)C1=C2O LIETVYHJBSLSSW-UHFFFAOYSA-N 0.000 description 1
- HQFSNUYUXXPVKL-UHFFFAOYSA-N 4-[(4-fluorophenyl)methyl]-2-[1-(2-phenylethyl)azepan-4-yl]phthalazin-1-one Chemical compound C1=CC(F)=CC=C1CC(C1=CC=CC=C1C1=O)=NN1C1CCN(CCC=2C=CC=CC=2)CCC1 HQFSNUYUXXPVKL-UHFFFAOYSA-N 0.000 description 1
- OUQPTBCOEKUHBH-LSDHQDQOSA-N 4-[2-[4-[(E)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]phenoxy]ethyl]morpholine Chemical compound C=1C=C(C(CCC2(C)C)(C)C)C2=CC=1C(/C)=C/C(C=C1)=CC=C1OCCN1CCOCC1 OUQPTBCOEKUHBH-LSDHQDQOSA-N 0.000 description 1
- HPLNQCPCUACXLM-PGUFJCEWSA-N 4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide Chemical compound C([C@@H](CCN(C)C)NC=1C(=CC(=CC=1)S(=O)(=O)NC(=O)C=1C=CC(=CC=1)N1CCN(CC=2C(=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1)[N+]([O-])=O)SC1=CC=CC=C1 HPLNQCPCUACXLM-PGUFJCEWSA-N 0.000 description 1
- VAZAPHZUAVEOMC-UHFFFAOYSA-N 4-acetamido-N-(2-aminophenyl)benzamide Chemical compound C1=CC(NC(=O)C)=CC=C1C(=O)NC1=CC=CC=C1N VAZAPHZUAVEOMC-UHFFFAOYSA-N 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N 4-hydroxy-3-(3-oxo-1-phenylbutyl)-1-benzopyran-2-one Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- NSUDGNLOXMLAEB-UHFFFAOYSA-N 5-(2-formyl-3-hydroxyphenoxy)pentanoic acid Chemical compound OC(=O)CCCCOC1=CC=CC(O)=C1C=O NSUDGNLOXMLAEB-UHFFFAOYSA-N 0.000 description 1
- PXLPCZJACKUXGP-UHFFFAOYSA-N 5-(3,4-dichlorophenyl)-6-ethylpyrimidine-2,4-diamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 PXLPCZJACKUXGP-UHFFFAOYSA-N 0.000 description 1
- XESARGFCSKSFID-FLLFQEBCSA-N 5-[(2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1H-pyrazole-3-carboxamide Chemical compound OC1=C(C(=O)N)NN=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 XESARGFCSKSFID-FLLFQEBCSA-N 0.000 description 1
- APNRZHLOPQFNMR-WEIUTZTHSA-N 5-[(E)-5-[(1S)-2,2-dimethyl-6-methylidenecyclohexyl]-3-methylpent-2-enyl]phenazin-1-one Chemical compound C12=CC=CC=C2N=C(C(C=CC=2)=O)C=2N1C\C=C(/C)CC[C@@H]1C(=C)CCCC1(C)C APNRZHLOPQFNMR-WEIUTZTHSA-N 0.000 description 1
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 1
- ZCJXQWYMBJYJNB-LRDBBFHQSA-N 5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline-2,4-diamine;(2S,3S,4S,5R)-2,3,4,5-tetrahydroxy-6-oxohexanoic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O.COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 ZCJXQWYMBJYJNB-LRDBBFHQSA-N 0.000 description 1
- PXBZKHOQHTVCSQ-QZTJIDSGSA-N 5-nitro-2-[(2R)-1-[2-[[(2R)-2-(5-nitro-1,3-dioxobenzo[de]isoquinolin-2-yl)propyl]amino]ethylamino]propan-2-yl]benzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N([C@@H](CNCCNC[C@@H](C)N2C(C=3C=C(C=C4C=CC=C(C=34)C2=O)[N+]([O-])=O)=O)C)C2=O)=O)=C3C2=CC=CC3=C1 PXBZKHOQHTVCSQ-QZTJIDSGSA-N 0.000 description 1
- BOJKULTULYSRAS-OTESTREVSA-N 5508-58-7 Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 description 1
- VJXSSYDSOJBUAV-UHFFFAOYSA-N 6-(2,5-Dimethoxy-Benzyl)-5-Methyl-Pyrido[2,3-D]Pyrimidine-2,4-Diamine Chemical compound COC1=CC=C(OC)C(CC=2C(=C3C(N)=NC(N)=NC3=NC=2)C)=C1 VJXSSYDSOJBUAV-UHFFFAOYSA-N 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N 6-(3-methyl-5-nitroimidazol-4-yl)sulfanyl-7H-purin-2-amine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- OTSZCHORPMQCBZ-UHFFFAOYSA-N 6-[(3-chlorophenyl)-imidazol-1-ylmethyl]-1H-benzimidazole;hydron;chloride Chemical compound Cl.ClC1=CC=CC(C(C=2C=C3NC=NC3=CC=2)N2C=NC=C2)=C1 OTSZCHORPMQCBZ-UHFFFAOYSA-N 0.000 description 1
- KXBCLNRMQPRVTP-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one Chemical compound O=C1NC(N)=CC2=C1N=CN2 KXBCLNRMQPRVTP-UHFFFAOYSA-N 0.000 description 1
- ZNTIXVYOBQDFFV-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.O=C1NC(N)=CC2=C1N=CN2 ZNTIXVYOBQDFFV-UHFFFAOYSA-N 0.000 description 1
- GZAJOEGTZDUSKS-UHFFFAOYSA-N 6-amino-3',6'-dihydroxyspiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound C12=CC=C(O)C=C2OC2=CC(O)=CC=C2C21OC(=O)C1=CC(N)=CC=C21 GZAJOEGTZDUSKS-UHFFFAOYSA-N 0.000 description 1
- GFYRZTLCYQQVHZ-UHFFFAOYSA-N 6-hydroxy-4-oxo-N-phenyl-2-sulfanylidene-1H-pyrimidine-5-carboxamide Chemical compound N1C(=S)NC(=O)C(C(=O)NC=2C=CC=CC=2)=C1O GFYRZTLCYQQVHZ-UHFFFAOYSA-N 0.000 description 1
- GOYNNCPGHOBFCK-UHFFFAOYSA-N 7-[4-(dimethylamino)-5-[(2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl)oxy]-6-methyloxan-2-yl]oxy-9-ethyl-4,6,9,10,11-pentahydroxy-8,10-dihydro-7H-tetracene-5,12-dione Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C(O)=C1C(OC3OC(C)C(OC4OC(C)C5OC6OC(C)C(=O)CC6OC5C4)C(C3)N(C)C)CC(CC)(O)C(O)C1=C2O GOYNNCPGHOBFCK-UHFFFAOYSA-N 0.000 description 1
- GOJJWDOZNKBUSR-UHFFFAOYSA-N 7-sulfamoyloxyheptyl sulfamate Chemical compound NS(=O)(=O)OCCCCCCCOS(N)(=O)=O GOJJWDOZNKBUSR-UHFFFAOYSA-N 0.000 description 1
- LPDLEICKXUVJHW-QJILNLRNSA-N 78NZ2PMP25 Chemical compound OS(O)(=O)=O.O([C@]12[C@H](OC(C)=O)[C@]3(CC)C=CCN4CC[C@@]5([C@H]34)[C@H]1N(C)C1=C5C=C(C(=C1)OC)[C@]1(C(=O)OC)C3=C(C4=CC=CC=C4N3)CCN3C[C@H](C1)C[C@@](C3)(O)CC)C(=O)N(CCCl)C2=O LPDLEICKXUVJHW-QJILNLRNSA-N 0.000 description 1
- QAWIHIJWNYOLBE-OKKQSCSOSA-N ACIVICIN Chemical compound OC(=O)[C@@H](N)[C@@H]1CC(Cl)=NO1 QAWIHIJWNYOLBE-OKKQSCSOSA-N 0.000 description 1
- 229950008427 ACIVICIN Drugs 0.000 description 1
- 102100001249 ALB Human genes 0.000 description 1
- 101710027066 ALB Proteins 0.000 description 1
- 102100018024 ANG Human genes 0.000 description 1
- 229960003272 ASPARAGINASE Drugs 0.000 description 1
- 229950004810 ATAMESTANE Drugs 0.000 description 1
- 101710034857 ATIC Proteins 0.000 description 1
- GZOSMCIZMLWJML-VJLLXTKPSA-N Abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 1
- 229960000583 Acetic Acid Drugs 0.000 description 1
- 229940091181 Aconitic Acid Drugs 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N Aconitic acid Chemical compound OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- SMPZPKRDRQOOHT-UHFFFAOYSA-N Acronine Chemical compound CN1C2=CC=CC=C2C(=O)C2=C1C(C=CC(C)(C)O1)=C1C=C2OC SMPZPKRDRQOOHT-UHFFFAOYSA-N 0.000 description 1
- 229950000616 Acronine Drugs 0.000 description 1
- 206010001019 Acute promyelocytic leukaemia Diseases 0.000 description 1
- DPGOLRILOKERAV-AAWJQDODSA-N Adecypenol Chemical compound OC1C(CO)=CCC1(O)N1C(N=CNC[C@H]2O)C2N=C1 DPGOLRILOKERAV-AAWJQDODSA-N 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 208000002353 Alcoholic Hepatitis Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229950010949 Ambamustine Drugs 0.000 description 1
- 229950004821 Ambomycin Drugs 0.000 description 1
- JKOQGQFVAUAYPM-UHFFFAOYSA-N Amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 1
- 229960001097 Amifostine Drugs 0.000 description 1
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N Anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N Anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- BOJKULTULYSRAS-QPSYGYIJSA-N Andrographolide Natural products C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1\[C@H](O)COC1=O BOJKULTULYSRAS-QPSYGYIJSA-N 0.000 description 1
- VGQOVCHZGQWAOI-HYUHUPJXSA-N Anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- IOASYARYEYRREA-LQAJYKIKSA-N Aphidicolin glycinate Chemical compound C1[C@]23[C@]4(C)CC[C@H](O)[C@](C)(CO)[C@H]4CC[C@@H]3C[C@@H]1[C@@](COC(=O)CN)(O)CC2 IOASYARYEYRREA-LQAJYKIKSA-N 0.000 description 1
- 229940046844 Aromatase inhibitors Drugs 0.000 description 1
- 210000001367 Arteries Anatomy 0.000 description 1
- 206010003284 Arthropathy Diseases 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010075389 Aspergillus restrictus MITF protein Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- PEPMWUSGRKINHX-TXTPUJOMSA-N Atamestane Chemical compound C1C[C@@H]2[C@@]3(C)C(C)=CC(=O)C=C3CC[C@H]2[C@@H]2CCC(=O)[C@]21C PEPMWUSGRKINHX-TXTPUJOMSA-N 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 229950006933 Atrimustine Drugs 0.000 description 1
- 241001263178 Auriparus Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- OXNAATCTZCSVKR-AVGVIDKOSA-N Axinastatin 2 Chemical compound C([C@H]1C(=O)N[C@H](C(=O)N[C@H](C(N2CCC[C@H]2C(=O)N[C@@H](C(=O)N[C@@H](CC(N)=O)C(=O)N2CCC[C@H]2C(=O)N1)C(C)C)=O)CC(C)C)C(C)C)C1=CC=CC=C1 OXNAATCTZCSVKR-AVGVIDKOSA-N 0.000 description 1
- ANLDPEXRVVIABH-WUUSPZRJSA-N Axinastatin 3 Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C(=O)N[C@@H](CC(N)=O)C(=O)N2CCC[C@H]2C(=O)N1)C(C)C)=O)[C@@H](C)CC)C1=CC=CC=C1 ANLDPEXRVVIABH-WUUSPZRJSA-N 0.000 description 1
- 229960002756 Azacitidine Drugs 0.000 description 1
- WUKZPHOXUVCQOR-UHFFFAOYSA-N Azasetron Chemical compound C1N(CC2)CCC2C1NC(=O)C1=CC(Cl)=CC2=C1OCC(=O)N2C WUKZPHOXUVCQOR-UHFFFAOYSA-N 0.000 description 1
- 229950005951 Azasetron Drugs 0.000 description 1
- MIXLRUYCYZPSOQ-HXPMCKFVSA-N Azatoxin Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H]3N2C(OC3)=O)=C1 MIXLRUYCYZPSOQ-HXPMCKFVSA-N 0.000 description 1
- 229950004295 Azotomycin Drugs 0.000 description 1
- 206010073480 B-cell prolymphocytic leukaemia Diseases 0.000 description 1
- 229950005567 BENZODEPA Drugs 0.000 description 1
- 229950002370 BISNAFIDE Drugs 0.000 description 1
- 206010060945 Bacterial infection Diseases 0.000 description 1
- XYUFCXJZFZPEJD-PGRDOPGGSA-N Balanol Chemical compound OC(=O)C1=CC=CC(O)=C1C(=O)C1=C(O)C=C(C(=O)O[C@H]2[C@H](CNCCC2)NC(=O)C=2C=CC(O)=CC=2)C=C1O XYUFCXJZFZPEJD-PGRDOPGGSA-N 0.000 description 1
- XFILPEOLDIKJHX-QYZOEREBSA-N Batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 1
- 229950001858 Batimastat Drugs 0.000 description 1
- 208000009137 Behcet Syndrome Diseases 0.000 description 1
- 201000008335 Behcet's disease Diseases 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Belustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- QGJZLNKBHJESQX-FZFNOLFKSA-N Betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 description 1
- QGJZLNKBHJESQX-CASBDLHJSA-N Betulinic acid Natural products O=C(O)[C@@]12[C@@H]([C@@H](C(=C)C)CC1)[C@@H]1[C@](C)([C@@]3(C)[C@@H]([C@]4(C)[C@H](C(C)(C)[C@@H](O)CC4)CC3)CC1)CC2 QGJZLNKBHJESQX-CASBDLHJSA-N 0.000 description 1
- 108010005144 Bevacizumab Proteins 0.000 description 1
- 229940087430 Biaxin Drugs 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 108010071919 Bispecific Antibodies Proteins 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 210000000601 Blood Cells Anatomy 0.000 description 1
- 230000035639 Blood Levels Effects 0.000 description 1
- 210000004204 Blood Vessels Anatomy 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 240000000772 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 208000009899 Burkitt Lymphoma Diseases 0.000 description 1
- 239000004358 Butane-1, 3-diol Substances 0.000 description 1
- KJQFBVYMGADDTQ-UHFFFAOYSA-N Buthionine sulfoximine Chemical compound CCCCS(=N)(=O)CCC(N)C(O)=O KJQFBVYMGADDTQ-UHFFFAOYSA-N 0.000 description 1
- 240000001546 Byrsonima crassifolia Species 0.000 description 1
- 235000003197 Byrsonima crassifolia Nutrition 0.000 description 1
- ZIWXKGQDQBLUMV-JUDXGUMMSA-N C(C)(=O)[C@@]1([C@]([C@@](O[C@@H]1CO)(N1C(=O)NC(=O)C=C1)C(C)=O)(O)C(C)=O)O Chemical compound C(C)(=O)[C@@]1([C@]([C@@](O[C@@H]1CO)(N1C(=O)NC(=O)C=C1)C(C)=O)(O)C(C)=O)O ZIWXKGQDQBLUMV-JUDXGUMMSA-N 0.000 description 1
- 229960005084 CALCITRIOL Drugs 0.000 description 1
- 229940084030 CARBOXYMETHYLCELLULOSE CALCIUM Drugs 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N CARUBICIN Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- 229950001725 CARUBICIN Drugs 0.000 description 1
- HZCWPKGYTCJSEB-UHFFFAOYSA-N CHEMBL118841 Chemical compound C12=CC(OC)=CC=C2NC2=C([N+]([O-])=O)C=CC3=C2C1=NN3CCCN(C)C HZCWPKGYTCJSEB-UHFFFAOYSA-N 0.000 description 1
- FVLVBPDQNARYJU-KYZUINATSA-N CHEMBL1967746 Chemical compound C[C@H]1CC[C@H](NC(=O)N(CCCl)N=O)CC1 FVLVBPDQNARYJU-KYZUINATSA-N 0.000 description 1
- RWXRJSRJIITQAK-ZSBIGDGJSA-N CHEMBL2105109 Chemical compound C12=CC=CC=C2NC(=O)N1C(=O)N[C@H](C1)C[C@H]2CC[C@@H]1N2C RWXRJSRJIITQAK-ZSBIGDGJSA-N 0.000 description 1
- 102300032292 CRBN_HUMAN (isoform 1) Human genes 0.000 description 1
- 229950007258 CRISNATOL Drugs 0.000 description 1
- LUEYTMPPCOCKBX-KWYHTCOPSA-N CURACIN-A Chemical compound C=CC[C@H](OC)CC\C(C)=C\C=C\CC\C=C/[C@@H]1CSC([C@H]2[C@H](C2)C)=N1 LUEYTMPPCOCKBX-KWYHTCOPSA-N 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N C[N+](C)(C)CCO Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- LWQQLNNNIPYSNX-UROSTWAQSA-N Calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 1
- 229960005069 Calcium Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L Calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 102000005702 Calcium-Activated Potassium Channels Human genes 0.000 description 1
- 108010045489 Calcium-Activated Potassium Channels Proteins 0.000 description 1
- IVFYLRMMHVYGJH-PVPPCFLZSA-N Calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 1
- 229950009823 Calusterone Drugs 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229950009338 Caracemide Drugs 0.000 description 1
- 229950005155 Carbetimer Drugs 0.000 description 1
- WNRZHQBJSXRYJK-UHFFFAOYSA-N Carboxyamidotriazole Chemical compound NC1=C(C(=O)N)N=NN1CC(C=C1Cl)=CC(Cl)=C1C(=O)C1=CC=C(Cl)C=C1 WNRZHQBJSXRYJK-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 210000000845 Cartilage Anatomy 0.000 description 1
- 102000005403 Casein Kinases Human genes 0.000 description 1
- 108010031425 Casein Kinases Proteins 0.000 description 1
- JDVVGAQPNNXQDW-WCMLQCRESA-N Castanospermine Natural products O[C@H]1[C@@H](O)[C@H]2[C@@H](O)CCN2C[C@H]1O JDVVGAQPNNXQDW-WCMLQCRESA-N 0.000 description 1
- JDVVGAQPNNXQDW-TVNFTVLESA-N Castinospermine Chemical compound C1[C@H](O)[C@@H](O)[C@H](O)[C@H]2[C@@H](O)CCN21 JDVVGAQPNNXQDW-TVNFTVLESA-N 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 108050004290 Cecropins Proteins 0.000 description 1
- 229950010667 Cedefingol Drugs 0.000 description 1
- 229920002301 Cellulose acetate Polymers 0.000 description 1
- 210000003679 Cervix Uteri Anatomy 0.000 description 1
- 210000003837 Chick Embryo Anatomy 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 229960004630 Chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N Chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- 229960001231 Choline Drugs 0.000 description 1
- 241000511343 Chondrostoma nasus Species 0.000 description 1
- 208000002691 Choroiditis Diseases 0.000 description 1
- 210000003483 Chromatin Anatomy 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 229950000634 Cicaprost Drugs 0.000 description 1
- MYSWGUAQZAJSOK-UHFFFAOYSA-N Ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N Clomifene Chemical class C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- GLESHRYLRAOJPS-DHCFDGJBSA-N Conagenin Chemical compound C[C@@H](O)[C@H](C)[C@@H](O)C(=O)N[C@@](C)(CO)C(O)=O GLESHRYLRAOJPS-DHCFDGJBSA-N 0.000 description 1
- 208000001590 Congenital Abnormality Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 208000010247 Contact Dermatitis Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 229940072645 Coumadin Drugs 0.000 description 1
- SBRXTSOCZITGQG-UHFFFAOYSA-N Crisnatol Chemical compound C1=CC=C2C(CNC(CO)(CO)C)=CC3=C(C=CC=C4)C4=CC=C3C2=C1 SBRXTSOCZITGQG-UHFFFAOYSA-N 0.000 description 1
- 206010011401 Crohn's disease Diseases 0.000 description 1
- 229960001681 Croscarmellose Sodium Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229960000913 Crospovidone Drugs 0.000 description 1
- PSNOPSMXOBPNNV-VVCTWANISA-N Cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- TYVRUMCYJWCOOO-TVEJMLEISA-N Cypemycin Chemical compound C1S\C=C/NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(C(C)CC)NC(=O)C(=C\C)/NC(=O)C(CO)NC(=O)CNC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C(C(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(C)NC(=O)C(NC(=O)C(\NC(=O)C1N(CCC1)C(=O)C(\NC(=O)C(C)NC(=O)C1N(CCC1)C(=O)C(\NC(=O)C(C)N(C)C)=C/C)=C/C)=C/C)C(C)C)CC1=CC=CC=C1 TYVRUMCYJWCOOO-TVEJMLEISA-N 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- 108009000097 DNA Replication Proteins 0.000 description 1
- 238000007702 DNA assembly Methods 0.000 description 1
- 239000003155 DNA primer Substances 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 108010084740 Daclizumab Proteins 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 229960000640 Dactinomycin Drugs 0.000 description 1
- 241000252212 Danio rerio Species 0.000 description 1
- 229940026692 Decadron Drugs 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 210000004207 Dermis Anatomy 0.000 description 1
- 229960004833 Dexamethasone phosphate Drugs 0.000 description 1
- BMKDZUISNHGIBY-ZETCQYMHSA-N Dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- 229960000605 Dexrazoxane Drugs 0.000 description 1
- FYGDTMLNYKFZSV-MRCIVHHJSA-N Dextrin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O[C@@H]1[C@@H](CO)OC(O[C@@H]2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-MRCIVHHJSA-N 0.000 description 1
- 229950010621 Dezaguanine Drugs 0.000 description 1
- KYHUYMLIVQFXRI-SJPGYWQQSA-N Didemnin B Chemical compound CN([C@H](CC(C)C)C(=O)N[C@@H]1C(=O)N[C@@H]([C@H](CC(=O)O[C@H](C(=O)[C@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(OC)=CC=2)C(=O)O[C@@H]1C)C(C)C)O)[C@@H](C)CC)C(=O)[C@@H]1CCCN1C(=O)[C@H](C)O KYHUYMLIVQFXRI-SJPGYWQQSA-N 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Didronel Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 206010061819 Disease recurrence Diseases 0.000 description 1
- CGHRJBLSXVCYQF-YXSUXZIUSA-N Dolasetron Chemical compound C1=CC=C[C]2C(C(O[C@@H]3C[C@@H]4C[C@@H]5C[C@@H](N4CC5=O)C3)=O)=CN=C21 CGHRJBLSXVCYQF-YXSUXZIUSA-N 0.000 description 1
- 229940115080 Doxil Drugs 0.000 description 1
- 229960002918 Doxorubicin Hydrochloride Drugs 0.000 description 1
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N Drostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 229950005133 Duazomycin Drugs 0.000 description 1
- 108010015776 EC 1.1.3.4 Proteins 0.000 description 1
- 229950011461 EDELFOSINE Drugs 0.000 description 1
- 229950001022 ENPROMATE Drugs 0.000 description 1
- 229960001904 EPIRUBICIN Drugs 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N EPIRUBICIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- 101700084039 EPO Proteins 0.000 description 1
- 208000002646 Eales disease Diseases 0.000 description 1
- 229950010033 Ebselen Drugs 0.000 description 1
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselenum Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 description 1
- 229950005678 Ecomustine Drugs 0.000 description 1
- 208000005679 Eczema Diseases 0.000 description 1
- MHFRGQHAERHWKZ-UHFFFAOYSA-N Edelfosine Chemical compound CCCCCCCCCCCCCCCCCCOCC(OC)COP([O-])(=O)OCC[N+](C)(C)C MHFRGQHAERHWKZ-UHFFFAOYSA-N 0.000 description 1
- 210000001513 Elbow Anatomy 0.000 description 1
- MGQRRMONVLMKJL-KWJIQSIXSA-N Elsamitrucin Chemical compound O1[C@H](C)[C@H](O)[C@H](OC)[C@@H](N)[C@H]1O[C@@H]1[C@](O)(C)[C@@H](O)[C@@H](C)O[C@H]1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-KWJIQSIXSA-N 0.000 description 1
- 229950002339 Elsamitrucin Drugs 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229950005450 Emitefur Drugs 0.000 description 1
- 229950010625 Enloplatin Drugs 0.000 description 1
- 210000002615 Epidermis Anatomy 0.000 description 1
- 229950004926 Epipropidine Drugs 0.000 description 1
- 229960003265 Epirubicin Hydrochloride Drugs 0.000 description 1
- 229950009537 Epristeride Drugs 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 229940082789 Erbitux Drugs 0.000 description 1
- KLEPCGBEXOCIGS-QPPBQGQZSA-N Erbulozole Chemical compound C1=CC(NC(=O)OCC)=CC=C1SC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C=CC(OC)=CC=2)OC1 KLEPCGBEXOCIGS-QPPBQGQZSA-N 0.000 description 1
- 229950001426 Erbulozole Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N Erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229960001433 Erlotinib Drugs 0.000 description 1
- 210000003238 Esophagus Anatomy 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229940012017 Ethylenediamine Drugs 0.000 description 1
- 229940009626 Etidronate Drugs 0.000 description 1
- ISVXIZFUEUVXPG-UHFFFAOYSA-N Etiopurpurin Chemical compound CC1C2(CC)C(C(=O)OCC)=CC(C3=NC(C(=C3C)CC)=C3)=C2N=C1C=C(N1)C(CC)=C(C)C1=CC1=C(CC)C(C)=C3N1 ISVXIZFUEUVXPG-UHFFFAOYSA-N 0.000 description 1
- 229960005293 Etodolac Drugs 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N Etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 210000002744 Extracellular Matrix Anatomy 0.000 description 1
- 210000001508 Eye Anatomy 0.000 description 1
- 102100001972 FH Human genes 0.000 description 1
- 229950010404 FOSTRIECIN Drugs 0.000 description 1
- 210000003195 Fascia Anatomy 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 229960001419 Fenoprofen Drugs 0.000 description 1
- RDJGLLICXDHJDY-UHFFFAOYSA-N Fenoprofen Chemical compound OC(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108010029961 Filgrastim Proteins 0.000 description 1
- 229960004177 Filgrastim Drugs 0.000 description 1
- 229950006000 Flezelastine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N Floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 Floxuridine Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N Flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229950005682 Flurocitabine Drugs 0.000 description 1
- 208000004463 Follicular Adenocarcinoma Diseases 0.000 description 1
- 229950004217 Forfenimex Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N Formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- UXTSQCOOUJTIAC-UHFFFAOYSA-N Fosquidone Chemical compound C=1N2CC3=CC=CC=C3C(C)C2=C(C(C2=CC=C3)=O)C=1C(=O)C2=C3OP(O)(=O)OCC1=CC=CC=C1 UXTSQCOOUJTIAC-UHFFFAOYSA-N 0.000 description 1
- 229950005611 Fosquidone Drugs 0.000 description 1
- 108010036781 Fumarate Hydratase Proteins 0.000 description 1
- 229940116332 GLUCOSE OXIDASE Drugs 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 229950004410 Galocitabine Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N Ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 229960002963 Ganciclovir Drugs 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 229960005144 Gemcitabine hydrochloride Drugs 0.000 description 1
- 210000004392 Genitalia Anatomy 0.000 description 1
- 229940080856 Gleevec Drugs 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N Glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 229960003180 Glutathione Drugs 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 210000003714 Granulocytes Anatomy 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 206010066476 Haematological malignancy Diseases 0.000 description 1
- 210000002216 Heart Anatomy 0.000 description 1
- 208000006050 Hemangiopericytoma Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 210000003958 Hematopoietic Stem Cells Anatomy 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 229960002897 Heparin Drugs 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N Heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N Heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 208000007514 Herpes Zoster Diseases 0.000 description 1
- BNQSTAOJRULKNX-UHFFFAOYSA-N Hexamethylene bisacetamide Chemical compound CC(=O)NCCCCCCNC(C)=O BNQSTAOJRULKNX-UHFFFAOYSA-N 0.000 description 1
- 102000017286 Histone H2A Human genes 0.000 description 1
- 108050005231 Histone H2A Proteins 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 206010020583 Hypercalcaemia Diseases 0.000 description 1
- MPGWGYQTRSNGDD-UHFFFAOYSA-N Hypericin Chemical compound OC1=CC(O)=C(C2=O)C3=C1C1C(O)=CC(=O)C(C4=O)=C1C1=C3C3=C2C(O)=CC(C)=C3C2=C1C4=C(O)C=C2C MPGWGYQTRSNGDD-UHFFFAOYSA-N 0.000 description 1
- BTXNYTINYBABQR-UHFFFAOYSA-N Hypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(C)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 BTXNYTINYBABQR-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010051151 Hyperviscosity syndrome Diseases 0.000 description 1
- 101700030371 IDH2 Proteins 0.000 description 1
- 102100002772 IDH2 Human genes 0.000 description 1
- 101700070228 IFN Proteins 0.000 description 1
- 101700066403 IFNA1 Proteins 0.000 description 1
- 102100014263 IGF1R Human genes 0.000 description 1
- 101700025802 IGF1R Proteins 0.000 description 1
- 229950007654 ITASETRON Drugs 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 229960001176 Idarubicin Hydrochloride Drugs 0.000 description 1
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 1
- 229950002248 Idoxifene Drugs 0.000 description 1
- 229950009926 Idramantone Drugs 0.000 description 1
- 229960001101 Ifosfamide Drugs 0.000 description 1
- NITYDPDXAAFEIT-DYVFJYSZSA-N Ilomastat Chemical compound C1=CC=C2C(C[C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)CC(=O)NO)=CNC2=C1 NITYDPDXAAFEIT-DYVFJYSZSA-N 0.000 description 1
- 210000001822 Immobilized Cells Anatomy 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 206010021972 Inflammatory bowel disease Diseases 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- UGQMRVRMYYASKQ-KMPDEGCQSA-N Inosine Natural products O[C@H]1[C@H](O)[C@@H](CO)O[C@@H]1N1C(N=CNC2=O)=C2N=C1 UGQMRVRMYYASKQ-KMPDEGCQSA-N 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 102000020344 Insulin-Like Growth Factor Binding Proteins Human genes 0.000 description 1
- 108091022066 Insulin-Like Growth Factor Binding Proteins Proteins 0.000 description 1
- 229960003521 Interferon Alfa-2a Drugs 0.000 description 1
- 229960003507 Interferon Alfa-2b Drugs 0.000 description 1
- 108010054698 Interferon Alfa-n3 Proteins 0.000 description 1
- 229940109242 Interferon Alfa-n3 Drugs 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 229940047122 Interleukins Drugs 0.000 description 1
- PDWUPXJEEYOOTR-UHFFFAOYSA-N Iobenguane Chemical compound NC(=N)NCC1=CC=CC(I)=C1 PDWUPXJEEYOOTR-UHFFFAOYSA-N 0.000 description 1
- 229950010897 Iproplatin Drugs 0.000 description 1
- GURKHSYORGJETM-WAQYZQTGSA-N Irinotecan hydrochloride Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
- 229960000779 Irinotecan hydrochloride Drugs 0.000 description 1
- 102000012011 Isocitrate Dehydrogenase Human genes 0.000 description 1
- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N Isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 208000009883 Joint Disease Diseases 0.000 description 1
- 102100001056 KITLG Human genes 0.000 description 1
- 101710028765 KITLG Proteins 0.000 description 1
- 210000002510 Keratinocytes Anatomy 0.000 description 1
- 208000005670 Keratitis sicca Diseases 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N Ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 210000003734 Kidney Anatomy 0.000 description 1
- 210000000822 Killer Cells, Natural Anatomy 0.000 description 1
- 210000003127 Knee Anatomy 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- GSDBGCKBBJVPNC-BYPYZUCNSA-N L-lombricine dizwitterion Chemical compound NC(=[NH2+])NCCOP([O-])(=O)OC[C@H]([NH3+])C([O-])=O GSDBGCKBBJVPNC-BYPYZUCNSA-N 0.000 description 1
- 108010043135 L-methionine gamma-lyase Proteins 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- ZHTRILQJTPJGNK-FYBAATNNSA-N LEINAMYCIN Chemical compound N([C@@H](C=1SC=C(N=1)\C=C/C=C/C(=O)[C@H](O)/C=C(C)/CC1)C)C(=O)C[C@@]21S(=O)SC(=O)[C@]2(C)O ZHTRILQJTPJGNK-FYBAATNNSA-N 0.000 description 1
- 229950005634 LOXORIBINE Drugs 0.000 description 1
- 229960000448 Lactic acid Drugs 0.000 description 1
- POCZBHBFCIWCCV-UHFFFAOYSA-N Lamellarin N Chemical compound C1=C(O)C(OC)=CC=C1C1=C2C3=CC(OC)=C(O)C=C3C=CN2C2=C1C(C=C(OC)C(O)=C1)=C1OC2=O POCZBHBFCIWCCV-UHFFFAOYSA-N 0.000 description 1
- 206010024190 Leiomyosarcomas Diseases 0.000 description 1
- 108010062867 Lenograstim Proteins 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000008456 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Diseases 0.000 description 1
- 208000001152 Leukemia, Prolymphocytic, B-Cell Diseases 0.000 description 1
- 208000005749 Leukemia, Promyelocytic, Acute Diseases 0.000 description 1
- 229940087875 Leukine Drugs 0.000 description 1
- 229940008250 Leuprolide Drugs 0.000 description 1
- 229940089022 Leuprolide Acetate Drugs 0.000 description 1
- KDQAABAKXDWYSZ-SDCRJXSCSA-N Leurosidine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-SDCRJXSCSA-N 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levotetramisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- UGFHIPBXIWJXNA-UHFFFAOYSA-N Liarozole Chemical compound ClC1=CC=CC(C(C=2C=C3NC=NC3=CC=2)N2C=NC=C2)=C1 UGFHIPBXIWJXNA-UHFFFAOYSA-N 0.000 description 1
- 210000003041 Ligaments Anatomy 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 229940059904 Light Mineral Oil Drugs 0.000 description 1
- RBBBWKUBQVARPL-SWQMWMPHSA-N Lissoclinamide 7 Chemical compound C([C@H]1C(=O)N2CCC[C@H]2C2=N[C@@H]([C@H](O2)C)C(=O)N[C@@H](C=2SC[C@H](N=2)C(=O)N[C@H](CC=2C=CC=CC=2)C=2SC[C@H](N=2)C(=O)N1)C(C)C)C1=CC=CC=C1 RBBBWKUBQVARPL-SWQMWMPHSA-N 0.000 description 1
- 229950008991 Lobaplatin Drugs 0.000 description 1
- 229950000909 Lometrexol Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N Lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N Losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 229950008745 Losoxantrone Drugs 0.000 description 1
- XDMHALQMTPSGEA-UHFFFAOYSA-N Losoxantrone hydrochloride Chemical compound Cl.Cl.OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO XDMHALQMTPSGEA-UHFFFAOYSA-N 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N Luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 208000009856 Lung Disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- RVFGKBWWUQOIOU-NDEPHWFRSA-N Lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 1
- 229950002654 Lurtotecan Drugs 0.000 description 1
- 206010025169 Lyme disease Diseases 0.000 description 1
- 206010025280 Lymphocytosis Diseases 0.000 description 1
- 208000006557 Lymphoma, B-Cell, Marginal Zone Diseases 0.000 description 1
- VQJHOPSWBGJHQS-UHFFFAOYSA-N METOPRINE, METHODICHLOROPHEN Chemical compound CC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 VQJHOPSWBGJHQS-UHFFFAOYSA-N 0.000 description 1
- 108060004872 MIF Proteins 0.000 description 1
- 229950010718 MOPIDAMOL Drugs 0.000 description 1
- 102100006003 MT3 Human genes 0.000 description 1
- 102100013322 MTOR Human genes 0.000 description 1
- 210000002540 Macrophages Anatomy 0.000 description 1
- 206010025412 Macular dystrophy congenital Diseases 0.000 description 1
- 229950001474 Maitansine Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 208000006178 Malignant Mesothelioma Diseases 0.000 description 1
- 206010073059 Malignant neoplasm of unknown primary site Diseases 0.000 description 1
- 206010026673 Malignant pleural effusion Diseases 0.000 description 1
- 208000003393 Mammary Paget's Disease Diseases 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N Marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229950008959 Marimastat Drugs 0.000 description 1
- 102000001544 Maspin Human genes 0.000 description 1
- 102000004318 Matrilysin Human genes 0.000 description 1
- 108090000855 Matrilysin Proteins 0.000 description 1
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 1
- 230000035888 Maximum plasma concentration Effects 0.000 description 1
- 229940041334 Meclofenamate Sodium Drugs 0.000 description 1
- 229960004296 Megestrol Acetate Drugs 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229960003846 Melengestrol Acetate Drugs 0.000 description 1
- UDKABVSQKJNZBH-DWNQPYOZSA-N Melengestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(=C)[C@](OC(=O)C)(C(C)=O)[C@@]1(C)CC2 UDKABVSQKJNZBH-DWNQPYOZSA-N 0.000 description 1
- 206010027193 Meningioma malignant Diseases 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 230000035633 Metabolized Effects 0.000 description 1
- 229960003058 Methotrexate Sodium Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N Metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N Mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N Miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 229940042472 Mineral Oil Drugs 0.000 description 1
- 229950008541 Mirimostim Drugs 0.000 description 1
- DRCJGCOYHLTVNR-ZUIZSQJWSA-N Mitindomide Chemical compound C1=C[C@@H]2[C@@H]3[C@H]4C(=O)NC(=O)[C@H]4[C@@H]3[C@H]1[C@@H]1C(=O)NC(=O)[C@H]21 DRCJGCOYHLTVNR-ZUIZSQJWSA-N 0.000 description 1
- 229950001314 Mitindomide Drugs 0.000 description 1
- 229950002137 Mitocarcin Drugs 0.000 description 1
- 229950000911 Mitogillin Drugs 0.000 description 1
- 229950007612 Mitomalcin Drugs 0.000 description 1
- 229960004857 Mitomycin Drugs 0.000 description 1
- 229950005715 Mitosper Drugs 0.000 description 1
- 229960000350 Mitotane Drugs 0.000 description 1
- 229960001156 Mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N Mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960004169 Mitoxantrone Hydrochloride Drugs 0.000 description 1
- 229950008012 Mofarotene Drugs 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- 201000009262 Mooren's ulcer Diseases 0.000 description 1
- VAZLWPAHMORDGR-UHFFFAOYSA-L Motexafin gadolinium Chemical compound C1=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=C1[N]1=CC3=[N]4[Gd]11(N56)(OC(=O)C)(OC(=O)C)[N]2=CC(C(C)=C2CCCO)=[N]1C2=CC6=C(CC)C(CC)=C5C=C4C(CCCO)=C3C VAZLWPAHMORDGR-UHFFFAOYSA-L 0.000 description 1
- ISYPMTHOLIXZHJ-UHFFFAOYSA-N Motexafin lutetium Chemical compound [Lu].CC(O)=O.CC(O)=O.C1=NC2=CC(OCCOCCOCCOC)=C(OCCOCCOCCOC)C=C2N=CC(C(=C2CCCO)C)=NC2=CC(C(CC)=C2CC)=NC2=CC2=C(CCCO)C(C)=C1N2 ISYPMTHOLIXZHJ-UHFFFAOYSA-N 0.000 description 1
- 210000004400 Mucous Membrane Anatomy 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 229960000951 Mycophenolic Acid Drugs 0.000 description 1
- 206010028549 Myeloid leukaemia Diseases 0.000 description 1
- 208000001491 Myopia Diseases 0.000 description 1
- 229940105132 Myristate Drugs 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N N',N'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- PAVKBQLPQCDVNI-UHFFFAOYSA-N N',N'-diethyl-N-(9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazol-1-yl)propane-1,3-diamine Chemical compound N1C2=CC=C(OC)C=C2C2=C1C(C)=C1C=CN=C(NCCCN(CC)CC)C1=C2C PAVKBQLPQCDVNI-UHFFFAOYSA-N 0.000 description 1
- QJMCKEPOKRERLN-UHFFFAOYSA-N N,3,4-trihydroxybenzamide Chemical compound ONC(=O)C1=CC=C(O)C(O)=C1 QJMCKEPOKRERLN-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- CRJGESKKUOMBCT-PMACEKPBSA-N N-[(2S,3S)-1,3-dihydroxyoctadecan-2-yl]acetamide Chemical compound CCCCCCCCCCCCCCC[C@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-PMACEKPBSA-N 0.000 description 1
- NKFHKYQGZDAKMX-PPRKPIOESA-N N-[(E)-1-[(2S,4S)-4-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]ethylideneamino]benzamide;hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 NKFHKYQGZDAKMX-PPRKPIOESA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N N-[(E)-[10-[(E)-(4,5-dihydro-1H-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1H-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- TVYPSLDUBVTDIS-FUOMVGGVSA-N N-[1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]-3,4,5-trimethoxybenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NC=2C(=CN(C(=O)N=2)[C@H]2[C@@H]([C@H](O)[C@@H](C)O2)O)F)=C1 TVYPSLDUBVTDIS-FUOMVGGVSA-N 0.000 description 1
- ARKYUICTMUZVEW-UHFFFAOYSA-N N-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-[[4-[bis(2-chloroethyl)amino]benzoyl]amino]-1-methylpyrrole-2-carboxamide Chemical compound C1=C(C(=O)NCCC(N)=N)N(C)C=C1NC(=O)C1=CC(NC(=O)C=2N(C=C(NC(=O)C=3C=CC(=CC=3)N(CCCl)CCCl)C=2)C)=CN1C ARKYUICTMUZVEW-UHFFFAOYSA-N 0.000 description 1
- GWFRSQBGIGLMFD-BBKOCAQVSA-N N-[9-[(2R,3R,4S,5R)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-3,4-dihydroxyoxolan-2-yl]purin-6-yl]-2-phenoxyacetamide Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)(C=1C=CC=CC=1)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C3=NC=NC(NC(=O)COC=4C=CC=CC=4)=C3N=C2)O1 GWFRSQBGIGLMFD-BBKOCAQVSA-N 0.000 description 1
- HRXVDDOKERXBEY-UHFFFAOYSA-N N-[bis(aziridin-1-yl)phosphoryl]-N-ethyl-1,3,4-thiadiazol-2-amine Chemical compound C1CN1P(=O)(N1CC1)N(CC)C1=NN=CS1 HRXVDDOKERXBEY-UHFFFAOYSA-N 0.000 description 1
- WRINSSLBPNLASA-FOCLMDBBSA-N N-methyl-N-[(E)-(N-methylanilino)diazenyl]aniline Chemical compound C=1C=CC=CC=1N(C)\N=N\N(C)C1=CC=CC=C1 WRINSSLBPNLASA-FOCLMDBBSA-N 0.000 description 1
- 210000004693 NK cell Anatomy 0.000 description 1
- 108010021717 Nafarelin Proteins 0.000 description 1
- 229960002333 Nafarelin Drugs 0.000 description 1
- 206010028698 Nail dystrophy Diseases 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N Naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 Naloxone Drugs 0.000 description 1
- JZGDNMXSOCDEFQ-UHFFFAOYSA-N Napavin Chemical compound C1C(CC)(O)CC(C2)CN1CCC(C1=CC=CC=C1N1)=C1C2(C(=O)OC)C(C(=C1)OC)=CC2=C1N(C)C1C2(C23)CCN3CC=CC2(CC)C(O)C1(O)C(=O)NCCNC1=CC=C(N=[N+]=[N-])C=C1[N+]([O-])=O JZGDNMXSOCDEFQ-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N Naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229950010676 Nartograstim Drugs 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 210000003739 Neck Anatomy 0.000 description 1
- 229950007221 Nedaplatin Drugs 0.000 description 1
- 229950010159 Nemorubicin Drugs 0.000 description 1
- QZGIWPZCWHMVQL-UIYAJPBUSA-N Neocarzinostatin Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- PUUSSSIBPPTKTP-UHFFFAOYSA-N Neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 description 1
- 229940029345 Neupogen Drugs 0.000 description 1
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 1
- 208000004235 Neutropenia Diseases 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N Nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- 229950006344 Nocodazole Drugs 0.000 description 1
- 101710003000 ORF1/ORF2 Proteins 0.000 description 1
- 229950000370 OXISURAN Drugs 0.000 description 1
- RFTSSZJZXOSICM-VXLYETTFSA-N Obatoclax Chemical compound COC1=CC(C=2NC3=CC=CC=C3C=2)=N\C1=C\C=1NC(C)=CC=1C RFTSSZJZXOSICM-VXLYETTFSA-N 0.000 description 1
- 229950006584 Obatoclax Drugs 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 229960002700 Octreotide Drugs 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 229950011093 Onapristone Drugs 0.000 description 1
- ZLLOIFNEEWYATC-XMUHMHRVSA-N Osaterone Chemical compound C1=C(Cl)C2=CC(=O)OC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 ZLLOIFNEEWYATC-XMUHMHRVSA-N 0.000 description 1
- 229950006466 Osaterone Drugs 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 229940043515 Other immunoglobulins in ATC Drugs 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N Oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 229950000039 PELDESINE Drugs 0.000 description 1
- 229950003180 PEPLOMYCIN Drugs 0.000 description 1
- 102100007677 PFKFB3 Human genes 0.000 description 1
- 101710030069 PFKFB3 Proteins 0.000 description 1
- 229960000540 POLACRILIN POTASSIUM Drugs 0.000 description 1
- 108060006601 PRM1 Proteins 0.000 description 1
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 1
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N PUROMYCIN Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 1
- 229950010131 PUROMYCIN Drugs 0.000 description 1
- VYOQBYCIIJYKJA-VORKOXQSSA-N Palau'amine Chemical compound N([C@@]12[C@@H](Cl)[C@@H]([C@@H]3[C@@H]2[C@]24N=C(N)N[C@H]2N2C=CC=C2C(=O)N4C3)CN)C(N)=N[C@H]1O VYOQBYCIIJYKJA-VORKOXQSSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ZFYKZAKRJRNXGF-XRZRNGJYSA-N Palmitoyl rhizoxin Chemical compound O1C(=O)C2OC2CC(CC(=O)O2)CC2C(C)\C=C\C2OC2(C)C(OC(=O)CCCCCCCCCCCCCCC)CC1C(C)C(OC)C(\C)=C\C=C\C(\C)=C\C1=COC(C)=N1 ZFYKZAKRJRNXGF-XRZRNGJYSA-N 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N Pamidronic acid Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- RDIMTXDFGHNINN-IKGGRYGDSA-N Panaxytriol Chemical compound CCCCCCC[C@H](O)[C@@H](O)CC#CC#C[C@H](O)C=C RDIMTXDFGHNINN-IKGGRYGDSA-N 0.000 description 1
- RDIMTXDFGHNINN-BRWVUGGUSA-N Panaxytriol Natural products CCCCCCC[C@@H](O)[C@H](O)CC#CC#C[C@H](O)C=C RDIMTXDFGHNINN-BRWVUGGUSA-N 0.000 description 1
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 1
- 206010033661 Pancytopenia Diseases 0.000 description 1
- 108010061219 Panitumumab Proteins 0.000 description 1
- 229950003440 Panomifene Drugs 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- 208000004788 Pars Planitis Diseases 0.000 description 1
- LPHSYQSMAGVYNT-UHFFFAOYSA-N Pazelliptine Chemical compound N1C2=CC=NC=C2C2=C1C(C)=C1C=CN=C(NCCCN(CC)CC)C1=C2 LPHSYQSMAGVYNT-UHFFFAOYSA-N 0.000 description 1
- 229950006361 Pazelliptine Drugs 0.000 description 1
- DOHVAKFYAHLCJP-UHFFFAOYSA-N Peldesine Chemical compound C1=2NC(N)=NC(=O)C=2NC=C1CC1=CC=CN=C1 DOHVAKFYAHLCJP-UHFFFAOYSA-N 0.000 description 1
- 229950006960 Peliomycin Drugs 0.000 description 1
- 229960002340 Pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N Pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- 229960001476 Pentoxifylline Drugs 0.000 description 1
- WTWWXOGTJWMJHI-UHFFFAOYSA-N Perflubron Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br WTWWXOGTJWMJHI-UHFFFAOYSA-N 0.000 description 1
- 210000003800 Pharynx Anatomy 0.000 description 1
- 210000004214 Philadelphia Chromosome Anatomy 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N Phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 229960002139 Pilocarpine Hydrochloride Drugs 0.000 description 1
- QCHFTSOMWOSFHM-WPRPVWTQSA-N Pilopine HS Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N Pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 229950001030 Piritrexim Drugs 0.000 description 1
- KDRKQBMPDQDAJW-UHFFFAOYSA-N Piroxantrone Chemical compound OCCNCCN1NC2=C3C(=O)C=CC(=O)C3=C(O)C3=C2C1=CC=C3NCCCN KDRKQBMPDQDAJW-UHFFFAOYSA-N 0.000 description 1
- 229950001746 Piroxantrone Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N Piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 102000004211 Platelet factor 4 Human genes 0.000 description 1
- 108090000778 Platelet factor 4 Proteins 0.000 description 1
- 208000002151 Pleural Effusion Diseases 0.000 description 1
- 229960003171 Plicamycin Drugs 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 206010036030 Polyarthritis Diseases 0.000 description 1
- 239000004698 Polyethylene (PE) Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- 208000004358 Polyneuropathy Diseases 0.000 description 1
- 229960004293 Porfimer Sodium Drugs 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N Procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960001586 Procarbazine Hydrochloride Drugs 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- RJKFOVLPORLFTN-STHVQZNPSA-N Progesterone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC(=O)CC4)CC3)CC2)CC1 RJKFOVLPORLFTN-STHVQZNPSA-N 0.000 description 1
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010078762 Protein Precursors Proteins 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 208000010362 Protozoan Infections Diseases 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 210000004915 Pus Anatomy 0.000 description 1
- 229940076788 Pyruvate Drugs 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- NTHPAPBPFQJABD-LLVKDONJSA-N Ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 description 1
- 108090000231 Ras GTPase-activating proteins Proteins 0.000 description 1
- 102000003901 Ras GTPase-activating proteins Human genes 0.000 description 1
- 229920000297 Rayon Polymers 0.000 description 1
- 108010033725 Recombinant Proteins Proteins 0.000 description 1
- 102000007312 Recombinant Proteins Human genes 0.000 description 1
- 229940116176 Remicade Drugs 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038435 Renal failure Diseases 0.000 description 1
- 229950002225 Retelliptine Drugs 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 206010038932 Retinopathy Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 1
- WUAPFZMCVAUBPE-UHFFFAOYSA-N Rhenium Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N Rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 241000220010 Rhode Species 0.000 description 1
- 229920001914 Ribonucleotide Polymers 0.000 description 1
- 229940003641 Rituxan Drugs 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N Roquinimex Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- 102100017879 S100A9 Human genes 0.000 description 1
- 229950008902 SAFINGOL Drugs 0.000 description 1
- CGFVUVWMYIHGHS-UHFFFAOYSA-N SAINTOPIN Chemical compound C1=C(O)C=C2C=C(C(=O)C=3C(=C(O)C=C(C=3)O)C3=O)C3=C(O)C2=C1O CGFVUVWMYIHGHS-UHFFFAOYSA-N 0.000 description 1
- 108010005173 SERPIN-B5 Proteins 0.000 description 1
- 229950001403 SIZOFIRAN Drugs 0.000 description 1
- 229950007841 SULOFENUR Drugs 0.000 description 1
- 210000004761 Scalp Anatomy 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 241001243925 Sia Species 0.000 description 1
- 208000007056 Sickle Cell Anemia Diseases 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N Silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 241000713311 Simian immunodeficiency virus Species 0.000 description 1
- 229950009089 Simtrazene Drugs 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 208000004346 Smoldering Multiple Myeloma Diseases 0.000 description 1
- 240000001016 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229950004225 Sonermin Drugs 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- 229950004796 Sparfosic Acid Drugs 0.000 description 1
- XKLZIVIOZDNKEQ-CLQLPEFOSA-N Sparsomycin Chemical compound CSC[S@](=O)C[C@H](CO)NC(=O)\C=C\C1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-CLQLPEFOSA-N 0.000 description 1
- 229950009641 Sparsomycin Drugs 0.000 description 1
- YBZRLMLGUBIIDN-UHFFFAOYSA-N Spicamycin Chemical compound O1C(C(O)CO)C(NC(=O)CNC(=O)CCCCCCCCCCCCC(C)C)C(O)C(O)C1NC1=NC=NC2=C1NC=N2 YBZRLMLGUBIIDN-UHFFFAOYSA-N 0.000 description 1
- 229950004330 Spiroplatin Drugs 0.000 description 1
- 206010062113 Splenic marginal zone lymphoma Diseases 0.000 description 1
- 208000006045 Spondylarthropathy Diseases 0.000 description 1
- 206010052775 Spondyloarthropathy Diseases 0.000 description 1
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 1
- 229950001248 Squalamine Drugs 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 229960001052 Streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N Streptozotocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 210000004304 Subcutaneous Tissue Anatomy 0.000 description 1
- 229960005137 Succinic Acid Drugs 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N Suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 Suramin Drugs 0.000 description 1
- FXUAIOOAOAVCGD-FKSUSPILSA-N Swainsonine Chemical compound C1CC[C@H](O)[C@H]2[C@H](O)[C@H](O)CN21 FXUAIOOAOAVCGD-FKSUSPILSA-N 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Syngestrets Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 208000006379 Syphilis Diseases 0.000 description 1
- URLYINUFLXOMHP-HTVVRFAVSA-N TCN-P Chemical compound C=12C3=NC=NC=1N(C)N=C(N)C2=CN3[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O URLYINUFLXOMHP-HTVVRFAVSA-N 0.000 description 1
- 102100002607 TIMP1 Human genes 0.000 description 1
- 102100009534 TNF Human genes 0.000 description 1
- 101710040537 TNF Proteins 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 101700083014 TSC2 Proteins 0.000 description 1
- 102100008210 TSC2 Human genes 0.000 description 1
- 229950002687 Talisomycin Drugs 0.000 description 1
- 229950005667 Tallimustine Drugs 0.000 description 1
- VOKSWYLNZZRQPF-UHFFFAOYSA-N Talwin Chemical compound C1C2=CC=C(O)C=C2C2(C)C(C)C1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-UHFFFAOYSA-N 0.000 description 1
- 229950010168 Tauromustine Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 102000004591 Telomerase Human genes 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- RNVNXVVEDMSRJE-UHFFFAOYSA-N Teloxantrone hydrochloride Chemical compound Cl.Cl.OCCNCCN1NC2=C3C(=O)C=CC(=O)C3=C(O)C3=C2C1=CC=C3NCCNC RNVNXVVEDMSRJE-UHFFFAOYSA-N 0.000 description 1
- 229950008703 Teroxirone Drugs 0.000 description 1
- 206010043286 Terrien's marginal degeneration Diseases 0.000 description 1
- 210000001550 Testis Anatomy 0.000 description 1
- 229960005353 Testolactone Drugs 0.000 description 1
- 229940033529 Tetrahydrocannabinol Drugs 0.000 description 1
- WXZSUBHBYQYTNM-WMDJANBXSA-N Tetrazomine Chemical compound C=1([C@@H]2CO[C@@H]3[C@H]4C[C@@H](CO)[C@H](N4C)[C@@H](N23)CC=1C=C1)C(OC)=C1NC(=O)C1NCCC[C@H]1O WXZSUBHBYQYTNM-WMDJANBXSA-N 0.000 description 1
- UPGGKUQISSWRJJ-XLTUSUNSSA-N Thiocoraline Chemical compound O=C([C@H]1CSSC[C@@H](N(C(=O)CNC2=O)C)C(=O)N(C)[C@@H](C(SC[C@@H](C(=O)NCC(=O)N1C)NC(=O)C=1C(=CC3=CC=CC=C3N=1)O)=O)CSC)N(C)[C@H](CSC)C(=O)SC[C@@H]2NC(=O)C1=NC2=CC=CC=C2C=C1O UPGGKUQISSWRJJ-XLTUSUNSSA-N 0.000 description 1
- 229960005454 Thioguanine Drugs 0.000 description 1
- 206010043554 Thrombocytopenia Diseases 0.000 description 1
- 108010041111 Thrombopoietin Proteins 0.000 description 1
- 102000036902 Thrombopoietin Human genes 0.000 description 1
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N Thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 229950010183 Thymotrinan Drugs 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 229950011457 Tiamiprine Drugs 0.000 description 1
- FVRDYQYEVDDKCR-DBRKOABJSA-N Tiazofurin Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 1
- 210000004906 Toe nails Anatomy 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N Tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- TVPNFKRGOFJQOO-UHFFFAOYSA-N Topsentin B1 Chemical compound C1=CC=C2C(C3=CN=C(N3)C(=O)C=3C4=CC=C(C=C4NC=3)O)=CNC2=C1 TVPNFKRGOFJQOO-UHFFFAOYSA-N 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N Toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 206010044325 Trachoma Diseases 0.000 description 1
- 241000390203 Trachoma Species 0.000 description 1
- 229940116362 Tragacanth Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 108010010691 Trastuzumab Proteins 0.000 description 1
- 229950003873 Triciribine Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N Trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 Trimetrexate Drugs 0.000 description 1
- 102000007581 Tuberous Sclerosis Complex 2 Protein Human genes 0.000 description 1
- 108010007089 Tuberous Sclerosis Complex 2 Protein Proteins 0.000 description 1
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- ZHSGGJXRNHWHRS-VIDYELAYSA-N Tunicamycin Chemical compound O([C@H]1[C@@H]([C@H]([C@@H](O)[C@@H](CC(O)[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C(NC(=O)C=C2)=O)O)O1)O)NC(=O)/C=C/CC(C)C)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O ZHSGGJXRNHWHRS-VIDYELAYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N U-18,496 Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- 229950009811 UBENIMEX Drugs 0.000 description 1
- 102400000757 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N Uramustine Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- 210000003932 Urinary Bladder Anatomy 0.000 description 1
- 229960005356 Urokinase Drugs 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102100015313 VIP Human genes 0.000 description 1
- 101700003320 VIP Proteins 0.000 description 1
- 210000003462 Veins Anatomy 0.000 description 1
- 229950008261 Velaresol Drugs 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N Verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003895 Verteporfin Drugs 0.000 description 1
- 229960004982 Vinblastine Sulfate Drugs 0.000 description 1
- 229960002110 Vincristine Sulfate Drugs 0.000 description 1
- AQTQHPDCURKLKT-PNYVAJAMSA-N Vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-PNYVAJAMSA-N 0.000 description 1
- KLFUUCHXSFIPMH-YBFGSCICSA-N Vinepidine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@H](C2)CC)N2CCC2=C1NC1=CC=CC=C21 KLFUUCHXSFIPMH-YBFGSCICSA-N 0.000 description 1
- 229950001270 Vinepidine Drugs 0.000 description 1
- UNMODLJJNIJIBD-OTBVPMHJSA-N Vinglycinate sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 UNMODLJJNIJIBD-OTBVPMHJSA-N 0.000 description 1
- 229950009832 Vinleurosine Drugs 0.000 description 1
- 229960002166 Vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N VinorelbineTartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 206010047461 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047802 Waldenstrom's macroglobulinaemias Diseases 0.000 description 1
- 206010048214 Xanthoma Diseases 0.000 description 1
- 229950005561 ZANOTERONE Drugs 0.000 description 1
- 101710010406 ZBP14 Proteins 0.000 description 1
- MHDDZDPNIDVLNK-ZGIWMXSJSA-N Zanoterone Chemical compound C1C2=NN(S(C)(=O)=O)C=C2C[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CC[C@H]21 MHDDZDPNIDVLNK-ZGIWMXSJSA-N 0.000 description 1
- FYQZGCBXYVWXSP-STTFAQHVSA-N Zinostatin stimalamer Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1OC1C/2=C/C#C[C@H]3O[C@@]3([C@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(C)C=CC2=C(C)C=C(OC)C=C12 FYQZGCBXYVWXSP-STTFAQHVSA-N 0.000 description 1
- 229950009233 Zinostatin stimalamer Drugs 0.000 description 1
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 description 1
- ZMQRJWIYMXZORG-GZIFKOAOSA-N [(1E,3R,4R,6R,7Z,9Z,11E)-3,6,13-trihydroxy-3-methyl-1-[(2S)-6-oxo-2,3-dihydropyran-2-yl]trideca-1,7,9,11-tetraen-4-yl] dihydrogen phosphate Chemical compound OC/C=C/C=C\C=C/[C@H](O)C[C@@H](OP(O)(O)=O)[C@@](O)(C)\C=C\[C@@H]1CC=CC(=O)O1 ZMQRJWIYMXZORG-GZIFKOAOSA-N 0.000 description 1
- URRBLVUOXIGNQR-HXUWFJFHSA-N [(1R)-1-phenylethyl] N-(2-aminoethyl)-N-[(3-methoxy-4-phenylmethoxyphenyl)methyl]carbamate Chemical compound C1([C@@H](C)OC(=O)N(CCN)CC=2C=C(C(=CC=2)OCC=2C=CC=CC=2)OC)=CC=CC=C1 URRBLVUOXIGNQR-HXUWFJFHSA-N 0.000 description 1
- ZZWKZQDOSJAGGF-BVTJJHQYSA-N [(1S,2Z,7S,10Z,12R,13R,15S)-12-hydroxy-7-methyl-9-oxo-8-oxabicyclo[11.3.0]hexadeca-2,10-dien-15-yl] 2-(dimethylamino)acetate Chemical compound O[C@@H]1\C=C/C(=O)O[C@@H](C)CCC\C=C/[C@@H]2C[C@H](OC(=O)CN(C)C)C[C@H]21 ZZWKZQDOSJAGGF-BVTJJHQYSA-N 0.000 description 1
- SPKNARKFCOPTSY-XWPZMVOTSA-N [(2R,3S)-2-[(2S,3R)-3-methyloxiran-2-yl]-6-oxo-2,3-dihydropyran-3-yl] acetate Chemical compound C[C@H]1O[C@@H]1[C@H]1[C@@H](OC(C)=O)C=CC(=O)O1 SPKNARKFCOPTSY-XWPZMVOTSA-N 0.000 description 1
- VUPBDWQPEOWRQP-YDYCAPBPSA-N [(2R,3S,4S,5R,6R)-2-[(2R,3S,4S,5S,6S)-2-[(1R)-3-[[5-[[1-[[2-[4-[4-[[4-amino-6-[3-(4-aminobutylamino)propylamino]-6-oxohexyl]carbamoyl]-1,3-thiazol-2-yl]-1,3-thiazol-2-yl]-1-[(2S,3R,4R,5S,6S)-5-amino-3,4-dihydroxy-6-methyloxan-2-yl]oxy-2-hydroxyethyl]amino Chemical compound O([C@H]1[C@@H]([C@H](O)[C@H](N)[C@H](C)O1)O)C(C(O)C=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCC(N)CC(=O)NCCCNCCCCN)NC(=O)C(C(O)C)NC(=O)CC(O)C(C)NC(=O)C([C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)NC(=O)C1=NC(C(CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C VUPBDWQPEOWRQP-YDYCAPBPSA-N 0.000 description 1
- ZHHIHQFAUZZMTG-BSVJBJGJSA-N [(2R,3S,4S,5R,6R)-2-[(2R,3S,4S,5S,6S)-2-[(1R,2S)-2-[[6-amino-2-[(1S)-3-amino-1-[[(2S)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[[(2R,3S,4S)-3-hydroxy-5-[[(2S,3R)-3-hydroxy-1-oxo-1-[2-[4-[4-[3-[[(1S)-1-phenylethyl] Chemical compound OS(O)(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C ZHHIHQFAUZZMTG-BSVJBJGJSA-N 0.000 description 1
- IVCRCPJOLWECJU-WJTCVZFGSA-N [(7R,8R,9S,13S,14S,17S)-7,13-dimethyl-3-oxo-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1C[C@]2(C)[C@@H](OC(C)=O)CC[C@H]2[C@@H]2[C@H](C)CC3=CC(=O)CCC3[C@H]21 IVCRCPJOLWECJU-WJTCVZFGSA-N 0.000 description 1
- PQNNIEWMPIULRS-SUTYWZMXSA-N [(8E,10E,12E)-7-hydroxy-6-methyl-2-(3-methyl-6-oxo-2,3-dihydropyran-2-yl)tetradeca-8,10,12-trien-5-yl] dihydrogen phosphate Chemical compound C\C=C\C=C\C=C\C(O)C(C)C(OP(O)(O)=O)CCC(C)C1OC(=O)C=CC1C PQNNIEWMPIULRS-SUTYWZMXSA-N 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N [(8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-3-oxo-2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8R,9S,13S,14S,17S)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- XASGSSXPZXRXFL-UHFFFAOYSA-L [1-(aminomethyl)cyclohexyl]methanamine;platinum(2+);sulfate Chemical compound [Pt+2].[O-]S([O-])(=O)=O.NCC1(CN)CCCCC1 XASGSSXPZXRXFL-UHFFFAOYSA-L 0.000 description 1
- JJULHOZRTCDZOH-JGJFOBQESA-N [1-[[[(2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-3-octadecylsulfanylpropan-2-yl] hexadecanoate Chemical compound O[C@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(CSCCCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)O[C@H]1N1C(=O)N=C(N)C=C1 JJULHOZRTCDZOH-JGJFOBQESA-N 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- ASQRQYODAQUVBR-UHFFFAOYSA-L [4-(aminomethyl)oxan-4-yl]methanamine;cyclobutane-1,1-dicarboxylate;platinum(2+) Chemical compound [Pt+2].NCC1(CN)CCOCC1.[O-]C(=O)C1(C([O-])=O)CCC1 ASQRQYODAQUVBR-UHFFFAOYSA-L 0.000 description 1
- OCOKWVBYZHBHLU-UHFFFAOYSA-N [4-[2-[4-(2-methylpropoxycarbonyloxymethyl)-3,5-dioxopiperazin-1-yl]ethyl]-2,6-dioxopiperazin-1-yl]methyl 2-methylpropyl carbonate Chemical compound C1C(=O)N(COC(=O)OCC(C)C)C(=O)CN1CCN1CC(=O)N(COC(=O)OCC(C)C)C(=O)C1 OCOKWVBYZHBHLU-UHFFFAOYSA-N 0.000 description 1
- JURAJLFHWXNPHG-UHFFFAOYSA-N [acetyl(methylcarbamoyl)amino] N-methylcarbamate Chemical compound CNC(=O)ON(C(C)=O)C(=O)NC JURAJLFHWXNPHG-UHFFFAOYSA-N 0.000 description 1
- 229960000853 abiraterone Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- DEXPIBGCLCPUHE-UISHROKMSA-N acetic acid;(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2R)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5, Chemical compound CC(O)=O.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 DEXPIBGCLCPUHE-UISHROKMSA-N 0.000 description 1
- IAGMBSXKAGFBJT-UHFFFAOYSA-N acetic acid;1,4-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione Chemical compound CC(O)=O.O=C1C2=CC=CC=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO IAGMBSXKAGFBJT-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 230000001919 adrenal Effects 0.000 description 1
- 201000005179 adrenal carcinoma Diseases 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N aminolevulinic acid Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- 229960001694 anagrelide Drugs 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitors Drugs 0.000 description 1
- 108010072788 angiogenin Proteins 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 108010070670 antarelix Proteins 0.000 description 1
- 230000002280 anti-androgenic Effects 0.000 description 1
- 230000001772 anti-angiogenic Effects 0.000 description 1
- 230000001833 anti-estrogenic Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 230000002097 anti-phospholipid Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940045985 antineoplastic drugs Platinum compounds Drugs 0.000 description 1
- 230000003078 antioxidant Effects 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 201000008804 arthropathy Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 201000004116 autosomal recessive non-syndromic intellectual disability Diseases 0.000 description 1
- 108010093000 axinastatin 2 Proteins 0.000 description 1
- 108010092978 axinastatin 3 Proteins 0.000 description 1
- OPWOOOGFNULJAQ-UHFFFAOYSA-L azane;cyclopentanamine;2-hydroxybutanedioate;platinum(2+) Chemical compound N.[Pt+2].NC1CCCC1.[O-]C(=O)C(O)CC([O-])=O OPWOOOGFNULJAQ-UHFFFAOYSA-L 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- OVMSOCFBDVBLFW-VHLOTGQHSA-N baccatin III derivatives Chemical class [H][C@]12[C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C([C@@H](OC(C)=O)C(=O)[C@]1(C)[C@@H](O)C[C@H]1OC[C@@]21OC(C)=O)C3(C)C OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 description 1
- VFIUCBTYGKMLCM-UHFFFAOYSA-N benzyl N-[bis(aziridin-1-yl)phosphoryl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NP(=O)(N1CC1)N1CC1 VFIUCBTYGKMLCM-UHFFFAOYSA-N 0.000 description 1
- 125000003460 beta-lactamyl group Chemical class 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N bondronat Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N cAMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 229960004649 calcipotriene Drugs 0.000 description 1
- 229960002882 calcipotriol Drugs 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2S)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- LSUTUUOITDQYNO-UHFFFAOYSA-N calphostin C Chemical compound C=12C3=C4C(CC(C)OC(=O)C=5C=CC=CC=5)=C(OC)C(O)=C(C(C=C5OC)=O)C4=C5C=1C(OC)=CC(=O)C2=C(O)C(OC)=C3CC(C)OC(=O)OC1=CC=C(O)C=C1 LSUTUUOITDQYNO-UHFFFAOYSA-N 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 201000009030 carcinoma Diseases 0.000 description 1
- 230000000271 cardiovascular Effects 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 229930016259 castanospermine Natural products 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 229920002092 cellular RNA Polymers 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- SBNPWPIBESPSIF-MHWMIDJBSA-N cetrorelix Chemical compound C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 SBNPWPIBESPSIF-MHWMIDJBSA-N 0.000 description 1
- 229960003230 cetrorelix Drugs 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229960004407 chorionic gonadotrophin Drugs 0.000 description 1
- 230000002759 chromosomal Effects 0.000 description 1
- 201000006934 chronic myeloid leukemia Diseases 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 150000004814 combretastatins Chemical class 0.000 description 1
- 230000002860 competitive Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 201000006233 congestive heart failure Diseases 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 108010006226 cryptophycin Proteins 0.000 description 1
- 108010090203 cryptophycin 8 Proteins 0.000 description 1
- 210000004748 cultured cells Anatomy 0.000 description 1
- 108010041566 cypemycin Proteins 0.000 description 1
- 229950006614 cytarabine ocfosfate Drugs 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000001461 cytolytic Effects 0.000 description 1
- 102000023091 damaged DNA binding proteins Human genes 0.000 description 1
- 108091012554 damaged DNA binding proteins Proteins 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 201000004624 dermatitis Diseases 0.000 description 1
- 231100000080 dermatitis contact Toxicity 0.000 description 1
- 229960005408 deslorelin Drugs 0.000 description 1
- 230000001066 destructive Effects 0.000 description 1
- 229950001640 dexormaplatin Drugs 0.000 description 1
- 239000008356 dextrose and sodium chloride injection Substances 0.000 description 1
- 239000008355 dextrose injection Substances 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- SVJSWELRJWVPQD-UHFFFAOYSA-L disodium;2-[[4-[2-(2-amino-4-oxo-5,6,7,8-tetrahydro-1H-pyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C1NC=2NC(N)=NC(=O)C=2CC1CCC1=CC=C(C(=O)NC(CCC([O-])=O)C([O-])=O)C=C1 SVJSWELRJWVPQD-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960003413 dolasetron Drugs 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229940017743 dromostanolone propionate Drugs 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- 229950004683 drostanolone propionate Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 231100001003 eczema Toxicity 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000003073 embolic Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000000925 erythroid Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- XPGDODOEEWLHOI-GSDHBNRESA-N ethyl (2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)OCC)NC(=O)[C@@H](N)CC=1C=CC(F)=CC=1)C1=CC=CC(N(CCCl)CCCl)=C1 XPGDODOEEWLHOI-GSDHBNRESA-N 0.000 description 1
- HZQPPNNARUQMJA-IMIWJGOWSA-N ethyl N-[4-[[(2R,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methylsulfanyl]phenyl]carbamate;hydrochloride Chemical compound Cl.C1=CC(NC(=O)OCC)=CC=C1SC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 HZQPPNNARUQMJA-IMIWJGOWSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000003203 everyday Effects 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 201000001342 fallopian tube cancer Diseases 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000003328 fibroblastic Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000020375 flavoured syrup Nutrition 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 201000005160 follicular thyroid carcinoma Diseases 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002538 fungal Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037240 fusion proteins Human genes 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229960003794 ganirelix Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 101700048722 gef1 Proteins 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000007897 gelcap Substances 0.000 description 1
- OKKDEIYWILRZIA-OSZBKLCCSA-N gemcitabine hydrochloride Chemical compound [H+].[Cl-].O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 OKKDEIYWILRZIA-OSZBKLCCSA-N 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000002414 glycolytic Effects 0.000 description 1
- 150000002337 glycosamines Chemical group 0.000 description 1
- 230000003899 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 201000005569 gout Diseases 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 108010075381 growth inhibitory factor Proteins 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 201000010238 heart disease Diseases 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 201000002563 histoplasmosis Diseases 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 230000003054 hormonal Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- SOCGJDYHNGLZEC-UHFFFAOYSA-N hydron;N-methyl-N-[4-[(7-methyl-3H-imidazo[4,5-f]quinolin-9-yl)amino]phenyl]acetamide;chloride Chemical compound Cl.C1=CC(N(C(C)=O)C)=CC=C1NC1=CC(C)=NC2=CC=C(NC=N3)C3=C12 SOCGJDYHNGLZEC-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 229940027318 hydroxyurea Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 229940005608 hypericin Drugs 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 201000009794 idiopathic pulmonary fibrosis Diseases 0.000 description 1
- TZBDEVBNMSLVKT-UHFFFAOYSA-N idramantone Chemical compound C1C(C2)CC3CC1(O)CC2C3=O TZBDEVBNMSLVKT-UHFFFAOYSA-N 0.000 description 1
- 229960003696 ilomastat Drugs 0.000 description 1
- 230000002519 immonomodulatory Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000000984 immunochemical Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 230000003344 immunostimulant Effects 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000001506 immunosuppresive Effects 0.000 description 1
- 230000001771 impaired Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 201000009298 indolent myeloma Diseases 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000001524 infective Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 230000019734 interleukin-12 production Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 229960003795 iobenguane (123I) Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940075495 isopropyl palmitate Drugs 0.000 description 1
- 108010091711 kahalalide F Proteins 0.000 description 1
- 230000035984 keratolysis Effects 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960001739 lanreotide acetate Drugs 0.000 description 1
- 230000002045 lasting Effects 0.000 description 1
- 101700064822 lcb1 Proteins 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 229960002618 lenograstim Drugs 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 229950007056 liarozole Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000436 ligase inhibitor Substances 0.000 description 1
- 230000002197 limbic Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 108010020270 lissoclinamide 7 Proteins 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 230000001926 lymphatic Effects 0.000 description 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitors Drugs 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 208000009018 medullary Thyroid cancer Diseases 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- KPQJSSLKKBKWEW-RKDOVGOJSA-N methanesulfonic acid;5-nitro-2-[(2R)-1-[2-[[(2R)-2-(5-nitro-1,3-dioxobenzo[de]isoquinolin-2-yl)propyl]amino]ethylamino]propan-2-yl]benzo[de]isoquinoline-1,3-dione Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.[O-][N+](=O)C1=CC(C(N([C@@H](CNCCNC[C@@H](C)N2C(C=3C=C(C=C4C=CC=C(C=34)C2=O)[N+]([O-])=O)=O)C)C2=O)=O)=C3C2=CC=CC3=C1 KPQJSSLKKBKWEW-RKDOVGOJSA-N 0.000 description 1
- DASQOOZCTWOQPA-GXKRWWSZSA-L methotrexate disodium Chemical compound [Na+].[Na+].C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 DASQOOZCTWOQPA-GXKRWWSZSA-L 0.000 description 1
- FCGIVHSBEKGQMZ-UHFFFAOYSA-N methyl 2-(bromomethyl)-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1CBr FCGIVHSBEKGQMZ-UHFFFAOYSA-N 0.000 description 1
- CRZGFIMLHZTLGT-UHFFFAOYSA-N methyl 2-methyl-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1C CRZGFIMLHZTLGT-UHFFFAOYSA-N 0.000 description 1
- XGZVLEAZGCUUPH-UHFFFAOYSA-N methylamino(methylimino)methanesulfonic acid Chemical compound CNC(=NC)S(O)(=O)=O XGZVLEAZGCUUPH-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 229960003248 mifepristone Drugs 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 108010026677 mitomalcin Proteins 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- VOWOEBADKMXUBU-UHFFFAOYSA-J molecular oxygen;tetrachlorite;hydrate Chemical compound O.O=O.[O-]Cl=O.[O-]Cl=O.[O-]Cl=O.[O-]Cl=O VOWOEBADKMXUBU-UHFFFAOYSA-J 0.000 description 1
- 229960003063 molgramostim Drugs 0.000 description 1
- 108010032806 molgramostim Proteins 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000002864 mononuclear phagocyte Anatomy 0.000 description 1
- 229940035032 monophosphoryl lipid A Drugs 0.000 description 1
- 230000001002 morphogenetic Effects 0.000 description 1
- 230000000877 morphologic Effects 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 230000004379 myopia Effects 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-M myristate Chemical compound CCCCCCCCCCCCCC([O-])=O TUNFSRHWOTWDNC-UHFFFAOYSA-M 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 108010032539 nartograstim Proteins 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000037125 natural defense Effects 0.000 description 1
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 1
- 229950010733 neridronic acid Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 201000006039 nodal marginal zone lymphoma Diseases 0.000 description 1
- MAZYQGHSTXUZJF-ZBRHGPMOSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](O)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@]5(C)C[C@H](C[C@@H](O5)CC4=C3C3=O)N(C)C)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 MAZYQGHSTXUZJF-ZBRHGPMOSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 230000000683 nonmetastatic Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000020520 nucleotide-excision repair Effects 0.000 description 1
- 230000000414 obstructive Effects 0.000 description 1
- KREXGRSOTUKPLX-UHFFFAOYSA-N octadecanoic acid;zinc Chemical compound [Zn].CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O KREXGRSOTUKPLX-UHFFFAOYSA-N 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 230000004768 organ dysfunction Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 201000005170 papillary thyroid carcinoma Diseases 0.000 description 1
- 230000005298 paramagnetic Effects 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 229960003820 pentosan polysulfate sodium Drugs 0.000 description 1
- 229960001217 perflubron Drugs 0.000 description 1
- 229930007643 perillyl alcohol Natural products 0.000 description 1
- 235000005693 perillyl alcohol Nutrition 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- FXSKHQLAUMGYJK-UHFFFAOYSA-J platinum(4+);propan-2-amine;dichloride;dihydroxide Chemical compound [OH-].[OH-].[Cl-].[Cl-].[Pt+4].CC(C)N.CC(C)N FXSKHQLAUMGYJK-UHFFFAOYSA-J 0.000 description 1
- 108010049948 plitidepsin Proteins 0.000 description 1
- 229920000069 poly(p-phenylene sulfide) Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 230000001855 preneoplastic Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000000770 pro-inflamatory Effects 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- DERJYEZSLHIUKF-UHFFFAOYSA-N procarbazine hydrochloride Chemical compound Cl.CNNCC1=CC=C(C(=O)NC(C)C)C=C1 DERJYEZSLHIUKF-UHFFFAOYSA-N 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrugs Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UQOQENZZLBSFKO-POPPZSFYSA-N prostaglandin J2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)C=CC1=O UQOQENZZLBSFKO-POPPZSFYSA-N 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 230000002633 protecting Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 239000003806 protein tyrosine phosphatase inhibitor Substances 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic Effects 0.000 description 1
- 201000002154 pterygium Diseases 0.000 description 1
- 239000000784 purine nucleoside phosphorylase inhibitor Substances 0.000 description 1
- 230000001698 pyrogenic Effects 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 230000002285 radioactive Effects 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229950001588 ramosetron Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- 229940100552 retinamide Drugs 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 150000003291 riboses Chemical class 0.000 description 1
- 229920002033 ribozyme Polymers 0.000 description 1
- 229950003733 romurtide Drugs 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 231100000197 serious side effect Toxicity 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000002924 silencing RNA Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 230000001340 slower Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 201000009295 smoldering myeloma Diseases 0.000 description 1
- 229950010372 sobuzoxane Drugs 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- PHPHRWZFQRLJIA-UZUGEDCSSA-M sodium;(2S,3R,4S,5S,6R)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol;chloride Chemical compound [Na+].[Cl-].OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O PHPHRWZFQRLJIA-UZUGEDCSSA-M 0.000 description 1
- KISFEBPWFCGRGN-UHFFFAOYSA-M sodium;2-(2,4-dichlorophenoxy)ethyl sulfate Chemical compound [Na+].[O-]S(=O)(=O)OCCOC1=CC=C(Cl)C=C1Cl KISFEBPWFCGRGN-UHFFFAOYSA-M 0.000 description 1
- OGPIIGMUPMPMNT-UHFFFAOYSA-M sodium;2-(2,6-dichloro-3-methylanilino)benzoate Chemical compound [Na+].CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C([O-])=O)=C1Cl OGPIIGMUPMPMNT-UHFFFAOYSA-M 0.000 description 1
- HZOREEUASZHZBI-UHFFFAOYSA-M sodium;2-phenylacetate Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1 HZOREEUASZHZBI-UHFFFAOYSA-M 0.000 description 1
- QUCDWLYKDRVKMI-UHFFFAOYSA-M sodium;3,4-dimethylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1C QUCDWLYKDRVKMI-UHFFFAOYSA-M 0.000 description 1
- PZOHOALJQOFNTB-UHFFFAOYSA-M sodium;6-fluoro-2-[4-(2-fluorophenyl)phenyl]-3-methylquinoline-4-carboxylate Chemical compound [Na+].N1=C2C=CC(F)=CC2=C(C([O-])=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PZOHOALJQOFNTB-UHFFFAOYSA-M 0.000 description 1
- XBUIKNRVGYFSHL-IAVQPKKASA-M sodium;[(1E,3R,4R,6R,7Z,9Z,11E)-3,6,13-trihydroxy-3-methyl-1-[(2R)-6-oxo-2,3-dihydropyran-2-yl]trideca-1,7,9,11-tetraen-4-yl] hydrogen phosphate Chemical compound [Na+].OC/C=C/C=C\C=C/[C@H](O)C[C@@H](OP(O)([O-])=O)[C@@](O)(C)\C=C\[C@H]1CC=CC(=O)O1 XBUIKNRVGYFSHL-IAVQPKKASA-M 0.000 description 1
- NSFFYSQTVOCNLX-JKIHJDPOSA-M sodium;[(2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl octadecyl phosphate;hydrate Chemical compound O.[Na+].O[C@H]1[C@H](O)[C@@H](COP([O-])(=O)OCCCCCCCCCCCCCCCCCC)O[C@H]1N1C(=O)N=C(N)C=C1 NSFFYSQTVOCNLX-JKIHJDPOSA-M 0.000 description 1
- 239000007905 soft elastic gelatin capsule Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- OTKJDMGTUTTYMP-ZWKOTPCHSA-N sphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@@H](N)CO OTKJDMGTUTTYMP-ZWKOTPCHSA-N 0.000 description 1
- 108010032486 splenopentin Proteins 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000002660 stem cell treatment Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 108091007018 stromelysin Proteins 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 229930003522 swainsonine Natural products 0.000 description 1
- 201000010874 syndrome Diseases 0.000 description 1
- 108010021891 tallimustine Proteins 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 230000003390 teratogenic Effects 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 108010062880 thiocoraline Proteins 0.000 description 1
- 229960004231 thymalfasin Drugs 0.000 description 1
- 201000005204 thyroid medullary carcinoma Diseases 0.000 description 1
- 229960003723 tiazofurine Drugs 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- FQYFLFUZRJOLBC-UHFFFAOYSA-N titanocene Chemical compound C12C3C4C5C1[Ti]16782345C2C7C6C1C82 FQYFLFUZRJOLBC-UHFFFAOYSA-N 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 201000005485 toxoplasmosis Diseases 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-M triacetate(1-) Chemical compound CC(=O)CC(=O)CC([O-])=O ILJSQTXMGCGYMG-UHFFFAOYSA-M 0.000 description 1
- HOGVTUZUJGHKPL-HTVVRFAVSA-N triciribine Chemical compound C=12C3=NC=NC=1N(C)N=C(N)C2=CN3[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O HOGVTUZUJGHKPL-HTVVRFAVSA-N 0.000 description 1
- 229960000538 trimetrexate glucuronate Drugs 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- 239000000225 tumor suppressor protein Substances 0.000 description 1
- 230000002476 tumorcidal Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- KDQAABAKXDWYSZ-JKDPCDLQSA-N vincaleukoblastine sulfate Chemical compound OS(O)(=O)=O.C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 KDQAABAKXDWYSZ-JKDPCDLQSA-N 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 201000007790 vitelliform macular dystrophy Diseases 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 201000006083 xeroderma pigmentosum Diseases 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/60—Complex ways of combining multiple protein biomarkers for diagnosis
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57426—Specifically defined cancers leukemia
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/5743—Specifically defined cancers of skin, e.g. melanoma
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
Abstract
Disclosed is a method of identifying a drug sensitive cancer patient in a group of cancer patients comprising: determining the expression level of cereblon (CRBN) in a biological sample of a cancer, which has been obtained from a cancer patient; predicting clinical response, monitoring clinical response, or monitoring patient compliance to dosing by a drug, based on the expression level of CRBN, wherein the cancer patients are diffuse large B-cell lymphoma patients; and wherein the drug is thalidomide, lenalidomide, pomalidomide or 3-(5-amino-2-methyl-4- oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. onse, or monitoring patient compliance to dosing by a drug, based on the expression level of CRBN, wherein the cancer patients are diffuse large B-cell lymphoma patients; and wherein the drug is thalidomide, lenalidomide, pomalidomide or 3-(5-amino-2-methyl-4- oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
Description
METHODS FOR THE ENT OF CANCER AND INFLAMMATORY
DISEASES USING CEREBLON AS A PREDICTOR
The present application claims priority to US. Provisional Patent Application Nos.
61/481,066, filed April 29, 2011; 61/511,986, filed July 26, 2011; and 61/579,600, filed
December 22, 2011; the ty of each of which is orated herein by reference.
1. FIELD
Provided herein are uses of the protein cereblon as a predictor of clinical sensitivity to
cancer and inflammatory diseases, and patient response to drug treatment.
2. BACKGROUND
2.1 Pathobiology of Cancer
Cancer is characterized ily by an increase in the number of abnormal cells derived
from a given normal , invasion of adjacent tissues by these abnormal cells, or lymphatic or
blood-bome spread of malignant cells to regional lymph nodes and to distant sites (metastasis).
Clinical data and molecular biologic studies indicate that cancer is a multistep s that
begins with minor preneoplastic changes, which may under certain conditions progress to
sia. The neoplastic lesion may evolve clonally and p an increasing capacity for
invasion, growth, metastasis, and heterogeneity, especially under conditions in which the
neoplastic cells escape the host’s immune surveillance. Roitt, 1., Brostoff, J and Kale, D.,
Immunology, 17. 1-17. 12 (3rd ed., Mosby, St. Louis, Mo., 1993).
There is an enormous variety of cancers which are described in detail in the medical
literature. Examples include cancers of the lung, colon, rectum, prostate, breast, brain, blood and
intestine. The incidence of cancer ues to climb as the general population ages, as new
cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively
exposed to sunlight) grow. However, options for the treatment of cancer are limited. For
example, in the case of blood cancers (e.g., multiple myeloma), few treatment options are
available, especially when conventional chemotherapy fails and arrow transplantation is
not an . A tremendous demand therefore exists for new s and compositions that
can be used to treat patients with cancer.
Many types of s are associated with new blood vessel formation, a process known
as angiogenesis. Several of the mechanisms involved in tumor-induced angiogenesis have been
elucidated. The most direct of these mechanisms is the secretion by the tumor cells of cytokines
with angiogenic properties. Examples of these cytokines include acidic and basic fibroblastic
growth factor (a,b-FGF), angiogenin, vascular endothelial growth factor (VEGF), and TNF-(x.
atively, tumor cells can release angiogenic peptides through the production of ses
and the subsequent breakdown of the extracellular matrix where some cytokines are stored (e.g.,
b-FGF). Angiogenesis can also be induced ctly through the recruitment of inflammatory
cells (particularly macrophages) and their subsequent release of angiogenic cytokines (e.g.,
TNF-u, b-FGF).
Lymphoma refers to s that ate in the lymphatic system. Lymphoma is characterized
by malignant neoplasms of lymphocytes—B lymphocytes and T cytes (z'.e., B-cells and
s). Lymphoma generally starts in lymph nodes or collections of lymphatic tissue in organs
including, but not limited to, the stomach or intestines. Lymphoma may involve the marrow and
the blood in some cases. Lymphoma may spread from one site to other parts of the body.
The treatment of various forms of lymphomas are described, for example, in US. patent no.
7,468,363, the entirety of which is incorporated herein by reference. Such lymphomas include,
but are not limited to, Hodgkin's lymphoma, dgkin's lymphoma, cutaneous B-cell
lymphoma, activated B-cell lymphoma, diffilse large B-cell lymphoma (DLBCL), mantle cell
lymphoma (MCL), follicular center lymphoma, transformed lymphoma, lymphocytic lymphoma
of intermediate differentiation, intermediate lymphocytic lymphoma (ILL), diffuse poorly
differentiated lymphocytic ma (PDL), centrocytic lymphoma, diffuse small-cleaved cell
lymphoma (DSCCL), peripheral T-cell lymphomas (PTCL), cutaneous T-Cell lymphoma and
mantle zone lymphoma and low grade follicular lymphoma.
dgkin's lymphoma (NHL) is the fifth most common cancer for both men and women in
the United States, with an estimated 63,190 new cases and 18,660 deaths in 2007. Jemal A, et al.,
CA Cancer J Clin 2007; 57(1):43-66. The ility of ping NHL increases with age and
the incidence ofNHL in the elderly has been steadily increasing in the past decade, causing
n with the aging trend of the US population. Id. Clarke C A, et al., Cancer 2002;
94(7):2015-2023.
e large B-cell lymphoma (DLBCL) ts for approximately one-third of non-
n’s lymphomas. While some DLBCL patients are cured with traditional chemotherapy,
the remainder die from the disease. Anticancer drugs cause rapid and tent ion of
lymphocytes, ly by direct apoptosis induction in mature T and B cells. See K. Stahnke. et
al., Blood 2001, 98:3066-3073. Absolute lymphocyte count (ALC) has been shown to be a
prognostic factor in follicular dgkin's lymphoma and recent results have suggested that
ALC at diagnosis is an important stic factor in diffuse large B-cell lymphoma.
The e large-B-cell lymphomas (DLBCL) can be divided into distinct lar subtypes
according to their gene profiling patterns: germinal-center B-cell—like DLBCL (GCB-DLBCL),
activated B-cell—like DLBCL (ABC-DLBCL), and primary mediastinal B-cell lymphoma
(PMBL) or sified type. These subtypes are characterized by distinct differences in survival,
chemo-responsiveness, and signaling pathway dependence, particularly the NF-KB pathway. See
D. Kim et al., Journal ofClinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I.
Vol 25, No. 18S (June 20 Supplement), 2007: 8082. See Bea S, et al., Blood 2005; 106: 3183-90;
Ngo V.N. et al., Nature 2011; 470: 115-9. Such differences have prompted the search for more
effective and subtype-specific treatment strategies in DLBCL.
Leukemia refers to malignant neoplasms of the blood-forming tissues. Various forms of
leukemias are described, for example, in US. patent no. 7,393,862 and US. provisional patent
application no. 60/380,842, filed May 17, 2002, the entireties of which are incorporated herein
by reference. Although viruses reportedly cause several forms of leukemia in animals, causes of
leukemia in humans are to a large extent n. The Merck Manual, 944-952 (17th ed. 1999).
Transformation to malignancy typically occurs in a single cell through two or more steps with
subsequent proliferation and clonal expansion. In some leukemias, specific chromosomal
translocations have been identified with consistent leukemic cell morphology and special clinical
features (e.g., translocations of 9 and 22 in chronic myelocytic leukemia, and of 15 and 17 in
acute promyelocytic leukemia). Acute leukemias are predominantly undifferentiated cell
populations and chronic leukemias more mature cell forms.
Acute leukemias are divided into lymphoblastic (ALL) and non-lymphoblastic (ANLL) types.
The Merck Manual, 946-949 (17th ed. 1999). They may be fiarther ided by their
morphologic and emical appearance according to the French-American-British (FAB)
classification or ing to their type and degree of differentiation. The use of specific B- and
T-cell and d-antigen monoclonal dies are most helpful for classification. ALL is
inantly a childhood disease which is established by laboratory findings and bone marrow
examination. ANLL, also known as acute myelogenous leukemia or acute myeloid leukemia
(AML), occurs at all ages and is the more common acute leukemia among ; it is the form
usually associated with irradiation as a causative agent.
Chronic leukemias are described as being lymphocytic (CLL) or myelocytic (CML). The Merck
Manual, 949-952 (17th ed. 1999). CLL is characterized by the ance of mature
lymphocytes in blood, bone marrow, and lymphoid organs. The hallmark of CLL is sustained,
absolute lymphocytosis (> 5,000/uL) and an increase of lymphocytes in the bone . Most
CLL patients also have clonal expansion of cytes with B-cell characteristics. CLL is a
disease of middle or old age. In CML, the characteristic feature is the predominance of
granulocytic cells of all stages of differentiation in blood, bone marrow, liver, , and other
organs. In the symptomatic patient at diagnosis, the total white blood cell (WBC) count is
usually about 200,000/uL, but may reach 1,000,000/uL. CML is relatively easy to diagnose
because of the presence of the Philadelphia chromosome.
Bone marrow stromal cells are well known to t CLL disease progression and resistance to
herapy. Disrupting the interactions between CLL cells and stromal cells is an additional
target of CLL chemotherapy.
In addition to the acute and chronic categorization, neoplasms are also categorized based upon
the cells giving rise to such disorder into precursor or peripheral. See e.g., US. patent
publication no. 2008/0051379, the disclosure of which is incorporated herein by reference in its
entirety. Precursor neoplasms include ALLs and lymphoblastic lymphomas and occur in
lymphocytes before they have differentiated into either a T- or B-cell. Peripheral neoplasms are
those that occur in lymphocytes that have differentiated into either T- or B-cells. Such peripheral
neoplasms include, but are not limited to, B-cell CLL, B-cell prolymphocytic leukemia,
plasmacytic lymphoma, mantle cell lymphoma, ular lymphoma, extranodal
marginal zone B-cell lymphoma of -associated lymphoid tissue, nodal marginal zone
lymphoma, splenic marginal zone lymphoma, hairy cell leukemia, plasmacytoma, diffuse large
B-cell lymphoma and Burkitt lymphoma. In over 95 percent of CLL cases, the clonal ion
is of a B cell lineage. See Cancer: Principles & Practice of Oncology (3rd Edition) (1989) (pp.
1843-1847). In less than 5 percent of CLL cases, the tumor cells have a T-cell phenotype.
Notwithstanding these fications, however, the pathological ment of normal
hematopoiesis is the hallmark of all leukemias.
le myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells
produce antibodies and play a key role in immune function. However, uncontrolled growth of
these cells leads to bone pain and res, anemia, infections, and other complications.
Multiple myeloma is the second most common hematological malignancy, although the exact
causes of multiple a remain unknown. Multiple myeloma causes high levels of proteins
in the blood, urine, and organs, including but not limited to M-protein and other
immunoglobulins (antibodies), albumin, and betamicroglobulin. M-protein, short for
monoclonal protein, also known as otein, is a particularly abnormal protein produced by
the myeloma plasma cells and can be found in the blood or urine of almost all patients with
multiple myeloma.
Skeletal symptoms, including bone pain, are among the most clinically significant symptoms of
multiple myeloma. Malignant plasma cells e osteoclast stimulating factors ding IL-1,
IL-6 and TNF) which cause calcium to be leached from bones causing lytic lesions;
hypercalcemia is another m. The osteoclast stimulating factors, also referred to as
cytokines, may prevent apoptosis, or death of myeloma cells. Fifty percent of patients have
radiologically detectable myeloma-related skeletal lesions at diagnosis. Other common clinical
symptoms for multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections, and
renal insufficiency.
Bone marrow stromal cells are well known to t le myeloma e progression and
resistance to chemotherapy. Disrupting the interactions between multiple myeloma cells and
stromal cells is an additional target of multiple myeloma chemotherapy.
Myelodysplastic syndrome (MDS) refers to a diverse group of hematopoietic stem cell disorders.
MDS is characterized by a cellular marrow with impaired morphology and maturation
(dysmyelopoiesis), peripheral blood cytopenias, and a variable risk of progression to acute
leukemia, resulting from ineffective blood cell production. See The Merck Manual 953 (17th ed.
1999) and List et al., 1990, J Clin. Oncol. . The treatment ofMDS using
immunomodulatory compounds is described in US. Patent Publication No. 2004/0220144, the
ty of which is hereby incorporated by reference.
Solid tumors are abnormal masses of tissue that may, but usually do not contain cysts or liquid
areas. Solid tumors may be benign (not cancer), or ant (cancer). Different types of solid
tumors are named for the type of cells that form them. Examples of types solid tumors include,
but are not limited to malignant melanoma, adrenal carcinoma, breast oma, renal cell
cancer, carcinoma of the pancreas, non-small-cell lung carcinoma (NSCLC) and carcinoma of
unknown primary. Drugs ly administered to patients with various types or stages of
solid tumors include, but are not limited to, celebrex, etoposide, cyclophosphamide, docetaxel,
apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a ation thereof.
While patients who achieve a complete remission after initial therapy have a good chance for
cure, less than 10% of those who do not respond or relapse achieve a cure or a response lasting
longer than 3 years. See Cemy T, et al., Ann Oncol 2002; 13 Suppl 4:211-216.
Rituximab is known to deplete normal host B cells. See M. Aklilu et al., Annals of Oncology
:1109-1114, 2004. The erm immunologic effects of B cell depletion with mab and
the characteristics of the reconstituting B cell pool in lymphoma patients are not well defined,
despite the widespread usage of this therapy. See Jennifer H. Anolik et al., Clinical Immunology,
vol. 122, issue 2, February 2007, pages 139-145.
The approach for patients with relapsed or refractory disease relies heavily on experimental
treatments followed by stem cell transplantation, which may not be appropriate for patients with
a poor performance status or advanced age. Therefore, a tremendous demand exists for new
methods that can be used to treat patients with NHL.
The link between cancer an altered cellular metabolism has been well established. See Cairns,
R.A., et al. Nature Rev., 2011, 11:85-95. Understanding tumor cell lism and the
associated genetic s thereofmay lead to the identification of improved s of cancer
treatment. Id. For example, tumor cell al and proliferation via increased glucose
metabolism has been linked to the PIK3 pathway, y mutations in tumor suppressor genes
such as PTEN activate tumor cell metabolism. Id. AKTl (a.k.a., PKB) stimulates glucose
metabolism associated with tumor cell growth by s interactions with PFKFB3, ENTPDS,
mTOR and TSC2 (a.k.a., tuberin). Id.
Transcription factors HIF1 and HIF2 are largely responsible for cellular response to low oxygen
ions often associated with tumors. Id. Once activated, HIF1 promotes tumor cell capacity
to carry out glycolysis. Id. Thus, inhibition of HIF1 may slow or reverse tumor cell metabolism.
Activation of HIFl has been linked to PI3K, tumor suppressor proteins such as VHL, succinate
dehydrogenase (SDH) and fumarate hydratase. Id. The oncogenic transcription factor MYC has
also been linked to tumor cell metabolism, specifically glycolysis. Id. MYC also promotes cell
proliferation by glutamine metabolic pathways. Id.
AMP-activated protein kinase (AMPK) fianctions as a metabolic check point which tumor cells
must overcome in order to proliferate. Id. Several mutations have been identified which suppress
AMPK signaling in tumor cells. See Shackelford, D.B. & Shaw, R.J., Nature Rev. Cancer, 2009,
9: 563-575. STKll has been identified as a tumor suppressor gene d to the role .
See Cairns, R.A., et al. Nature Rev., 2011, 11:85-95.
The transcription factor p53, a tumor ssor, also has an important role in the tion of
cellular metabolism. Id. The loss of p53 in tumor cells may be a significant contributor to
s in tumor cell metabolism to the glycolytic pathway. Id. The OCTl transcription factor,
another potential target for herapeutics, may cooperate with p53 in regulating tumor cell
metabolism. Id.
Pyruvate kinate M2 (PKM2) promotes changes in cellular metabolism which confer metabolic
advantages to cancer cells by supporting cell proliferation. Id. For e, lung cancer cells
which express PKM2 over PKMl have been found to have such an age. Id. In the clinic,
PKM2 has been identified as being overexpressed in a number of cancer types. Id. Thus PKM2
may be a useful biomarker for the early detection of .
Mutations in isocitrate dehydrogenases IDHl and IDH2 have been linked to tumorigenesis,
specifically, in glioblastoma and acute myeloid leukemia. See Mardis, E.R. et al., N. Engl. J.
Med, 2009, 361: 1058-1066; Parsons, D.W. et al., Science, 2008, 321: 1807-1812.
The incidence of cancer continues to climb as the general tion ages, as new cancers
develop, and as susceptible populations (e.g., people infected with AIDS, the elderly or
excessively exposed to sunlight) grow. A tremendous demand therefore exists for new methods,
treatments and compositions that can be used to treat patients with cancer including but not
limited to those with lymphoma, NHL, multiple myeloma, AML, ias, and solid tumors.
A variety of other diseases and disorders are also associated with, or characterized by,
undesired angiogenesis. For example, enhanced or lated enesis has been
implicated in a number of diseases and medical conditions including, but not limited to, ocular
neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, rubeosis
(neovascularization of the angle), viral diseases, genetic diseases, inflammatory diseases, allergic
es, fibrosis, tis and autoimmune diseases. Examples of such diseases and conditions
include, but are not limited to: diabetic retinopathy; retinopathy of urity; corneal graft
rejection; neovascular glaucoma; retrolental flbroplasia; and proliferative vitreoretinopathy.
Accordingly, compounds that can control and/or inhibit unwanted angiogenesis or inhibit
the production of certain cytokines, ing TNF-(x, may be useful in the treatment and
prevention of s diseases and conditions.
2.2 Inflammatory Diseases
Inflammation plays a fiandamental role in host defenses and the progression of immune-
mediated es. The inflammatory response is initiated in response to injury (e.g., trauma,
ia, and foreign particles) and ion (e.g., bacterial or viral infection) by a complex
cascade of events, including chemical mediators (e.g, cytokines and prostaglandins) and
inflammatory cells (e.g, ytes). The inflammatory response is characterized by increased
blood flow, increased capillary permeability, and the influx of phagocytic cells. These events
result in swelling, redness, warmth (altered heat patterns), and pus formation at the site of injury
or infection.
Cytokines and prostaglandins control the inflammatory response, and are released in an
ordered and imiting e into the blood or affected tissues. This e of cytokines and
prostaglandins increases the blood flow to the area of injury or ion, and may result in
redness and warmth. Some of these chemicals cause a leak of fluid into the tissues, resulting in
swelling. This protective process may stimulate nerves and cause pain. These changes, when
ing for a limited period in the relevant area, work to the benefit of the body.
Tumor necrosis factor alpha (TNF-(x) is a cytokine that is released primarily by
mononuclear phagocytes in response to immunostimulators. TNF-(x is capable of enhancing
most cellular ses, such as differentiation, recruitment, proliferation, and proteolytic
degradation. At low levels, TNF-(x confers protection against infective agents, tumors, and tissue
damage. But TNF-(x also has a role in many diseases. When administered to mammals or
humans, TNF-(x causes or aggravates inflammation, fever, cardiovascular effects, hage,
coagulation, and acute phase responses similar to those seen during acute infections and shock
states. Enhanced or unregulated TNF-u production has been implicated in a number of diseases
and medical conditions, for example, s, such as solid tumors and blood-bome tumors;
heart disease, such as congestive heart failure; and viral, genetic, inflammatory, allergic, and
autoimmune diseases.
Adenosine 3',5'-cyclic monophosphate (cAMP) also plays a role in many diseases and
conditions, such as but not limited to asthma and inflammation, and other conditions (Lowe and
Cheng, Drugs oft/w Future, 17(9), 799-807, 1992). It has been shown that the ion of
cAMP in inflammatory leukocytes inhibits their activation and the subsequent release of
inflammatory ors, including TNF-u and NF-KB. Increased levels of cAMP also leads to
the relaxation of airway smooth .
A delicate well-balanced interplay between the l and cellular immune elements in
the atory response enables the elimination of harmful agents and the initiation of the
repair of damaged tissue. When this delicately balanced interplay is disrupted, the inflammatory
response may result in considerable damage to normal tissue and may be more harmful than the
original insult that ted the reaction. In these cases of uncontrolled atory responses,
clinical intervention is needed to prevent tissue damage and organ dysfunction. Diseases such as
sis, rheumatoid arthritis, osteoarthritis, psoriatic tis, s disease, asthma,
allergies or atory bowel disease, are characterized by chronic inflammation.
Inflammatory diseases such as arthritis, related arthritic conditions (e.g., osteoarthritis,
rheumatoid arthritis, and psoriatic arthritis), inflammatory bowel disease (e.g., Crohn's disease
and ulcerative s), , psoriasis, atopic dermatitis, contact dermatitis, and chronic
obstructive pulmonary disease, chronic inflammatory pulmonary diseases are also prevalent and
problematic ailments. Enhanced or unregulated TNF-(x production plays a central role in the
inflammatory response and the administration of their antagonists block chronic and acute
responses in animal models of inflammatory disease.
Arthritis is a ic autoimmune disease that can refer to a group of conditions
involving damage to the joints of the body. There are over 100 different forms of arthritis. The
most common form is osteoarthritis (degenerative joint disease) and other arthritis forms are
rheumatoid arthritis, psoriatic arthritis, and related autoimmune diseases such as lupus and gout.
Rheumatoid arthritis is characterized by a chronic inflammation of the joints. Both synovial
tissue and fluid are invaded by inflammatory cells which lead to cytokine production. T cells
and monocytes infiltrating the joints display an increased activation of Type 1 and 2 immune
response markers.
WO 49299
tic arthritis is a chronic inflammatory arthritic condition affecting the skin, the
joints, the ion sites of s, ligaments, and fascia. Gladman, Current Opinion in
Rheumatology, “Current concepts in psoriatic arthritis,” 2002, 14:361-366, and Ruddy et a1.,
Rheumatology, vol. 2., chapter 71, page 1071, 6th ed., 2001. Psoriatic arthritis is commonly
associated with psoriasis. Id. Approximately 7% of patients with psoriasis develop psoriatic
arthritis. The Merck Manual, 448 (17th ed., 1999). Psoriatic arthritis may appear in a variety of
clinical patterns. There are five general patterns of psoriatic arthritis: arthritis of the distal
interphalangeal joints, destructive arthritis, symmetric polyarthritis inguishable from
toid arthritis, asymmetric oligoarthritis, and spondyloarthropathy. Ruddy et al., page
1073. Psoriasis appears to precede the onset of tic arthritis in 60-80% of patients.
Occasionally, arthritis and psoriasis appear aneously. Cutaneous eruptions may be
preceded by the arthropathy.
Psoriasis is a chronic systemic autoimmune disease that appears on the skin. There are
five types of psoriasis: plaque, guttate, e, pustular and erythrodermic. The most common
form, plaque psoriasis, is commonly seen as red and white hues of scaly patches appearing on the
top first layer of the epidermis. Some patients, though, have no dermatological symptoms. In
plaque psoriasis, skin rapidly accumulates at these sites, which gives it a silvery-white
appearance. Plaques frequently occur on the skin of the elbows and knees, but can affect any
area, including the scalp, palms of hands and soles of feet, and genitals. In contrast to eczema,
psoriasis is more likely to be found on the outer side of the joint. The disorder is a chronic
recurring condition that varies in severity from minor localized patches to complete body
coverage. Fingemails and toenails are frequently affected (psoriatic nail dystrophy) and can be
seen as an isolated symptom. Psoriasis can also cause ation of the joints, which is
known as psoriatic arthritis. In psoriasis, one hypothesis is that T cells become active, migrate to
the dermis and trigger the release of cytokines, TNF-(x in particular, which causes inflammation
and the rapid proliferation of keratinocytes.
2.3 Compounds
A number of studies have been conducted with the aim of providing compounds that can safely
and effectively be used to treat es associated with al production of TNF-u. See, e.g.,
Marriott, J.B., et a1., Expert Opin. Biol. Ther., 2001, 1(4): 1-8; G.W. , et a1., JMed Chem.,
1996, : 240; and G.W. Muller, et a1., Bi00rg & Med Chem Lett., 1998, 8: 2669-
2674. Some studies have focused on a group of compounds selected for their capacity to
potently inhibit TNF-(x production by LPS stimulated PBMC. L.G. Corral, et al., Ann. Rheum.
Dis., 1999, ppl I) 1107-1113. These compounds show not only potent inhibition of TNF-u
but also marked inhibition of LPS induced monocyte ILlB and IL12 production. LPS induced
1L6 is also inhibited by such compounds, albeit lly. These compounds are potent
stimulators of LPS induced IL10. Id.
Compounds for the methods provided herein include, but are not limited to, the substituted 2-
(2,6-dioxopiperidinyl) phthalimides and substituted 2-(2,6-dioxopiperidinyl)
oxoisoindoles described in US. patent nos. 6,281,230 and 6,316,471, both to G.W. Muller, et al.
Still other specific nds disclosed herein belong to a class of isoindole-imides disclosed in
US. patent nos. 6,395,754, 554, 7,091,353, US. patent publication no. 2004/0029832, and
International Publication No. W0 98/54 1 70, each of which is incorporated herein by nce.
Thalidomide, lenalidomide and pomalidomide have shown remarkable responses in patients with
multiple myeloma, ma and other logical diseases such as myelodysplastic
syndrome. See Galustian C, et al., Expert Opin Pharmacother., 2009, 10: 125-133. These drugs
display a broad spectrum of activity, including anti-angiogenic properties, modulation of proinflammatory
cytokines, co-stimulation of T cells, increased NK cell toxicity, direct anti-tumor
effects and modulation of stem cell differentiation.
For e, thalidomide and lenalidomide have emerged as important s for the treatment
of multiple myeloma in newly diagnosed ts, in patients with advanced disease who have
failed chemotherapy or transplantation, and in patients with relapsed or refractory multiple
a. Lenalidomide in combination with dexamethasone has been approved for the
treatment of patients with multiple myeloma who have received at least one prior therapy.
Pomalidomide may also be administered in combination with dexamethasone. US. Patent
Publication No. 2004/0029832 Al, the disclosure of which is hereby orated in its entirety,
discloses the treatment of multiple myeloma.
Another compound ed herein is 3-(5-aminomethyloxo-4H-quinazolin-3 -yl)-
piperidine-2,6-dione (“Compound B”), which has the following structure:
gmNY
2012/035429
or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or rph thereof.
Compound B can be prepared according to the methods described in the es
provided herein or as described in US. Pat. No. 7,635,700, the disclosure of which is
incorporated herein by reference in its entirety. The compound can be also sized
ing to other methods apparent to those of skill in the art based upon the teaching herein.
In certain embodiments, Compound B is in a crystalline form described in US. Provisional Pat.
App. No. 61/451,806, filed March 11, 2011, which is incorporated herein by reference in its
entirety. In some embodiments, the hydrochloride salt of Compound B is used in the methods
provided herein. Methods of treating, preventing and/or managing cancers and other diseases
using Compound B are bed in US. Provisional Pat. App. No. 61/451,995, filed March 11,
2011, which is incorporated herein by reference in its entirety.
2.4 on
The n Cereblon (CRBN) is a 442-amino acid protein conserved from plant to human. In
humans, the CRBN gene has been fied as a candidate gene of an autosomal recessive
nonsyndromic mental retardation R). See Higgins, J.J. et al., Neurology, 2004,
63: 1927-193 1. CRBN was initially characterized as an RGS-containing novel n that
interacted with a calcium-activated potassium channel protein (SLOl) in the rat brain, and was
later shown to interact with a voltage-gated chloride channel (CIC-2) in the retina with AMPK7
and DDBl. See Jo, S. et al., J. Neurochem, 2005, 94:1212-1224; Hohberger B. et al., FEBS Lett,
2009, 583:633-637; Angers S. et al., Nature, 2006, 443:590-593. DDBl was ally
identified as a nucleotide excision repair protein that associates with damaged DNA binding
protein 2 (DDB2). Its defective activity causes the repair defect in the patients with xeroderma
pigmentosum complementation group E (XPE). DDBl also appears to function as a component
ofnumerous distinct DCX (DDBl-CUL4-X-box) E3 ubiquitin-protein ligase complexes which
mediate the ubiquitination and subsequent proteasomal degradation of target ns. CRBN
has also been identified as a target for the development of therapeutic agents for diseases of the
al . See A1.
Cereblon has recently been identified as a key molecular target that binds to thalidomide to cause
birth defects. See Ito, T. et al., Science, 2010, 327:1345-1350. DDBl was found to interact
with CRBN and, thus, was indirectly associated with thalidomide. Moreover, thalidomide was
2012/035429
able to inhibit auto-ubiquitination of CRBN in vitro, suggesting that thalidomide is an E3
tin-ligase inhibitor. Id. Importantly, this activity was ted by thalidomide in wild-
type cells, but not in cells with mutated CRBN binding sites that prevent thalidomide binding. Id.
The thalidomide binding site was mapped to a highly conserved C-terminal 104 amino acid
region in CRBN. Id. dual point s in CRBN, Y384A and W386A were both
defective for thalidomide binding, with the double point mutant haVing the lowest thalidomide-
binding ty. Id. A link between CRBN and the teratogenic effect of thalidomide was
confirmed in animal models of zebra-fish and chick embryos. Id.
Whether binding to CRBN, the CRBN E3 ubiquitin-ligase complex, or one or more substrates of
CRBN, is required for the beneficial effects of thalidomide and other drugs is yet to be
established. Understanding these interactions with thalidomide and other drug targets will allow
the definition of the lar mechanisms of efficacy and/or toxicity and may lead to drugs
with improved efficacy and toxicity profiles.
2.5 Methods of Treating Cancer
Current cancer therapy may involve surgery, chemotherapy, hormonal therapy and/or
radiation treatment to eradicate neoplastic cells in a patient (see, for example, Stockdale, 1998,
Medicine, vol. 3, Rubenstein and an, eds., Chapter 12, Section IV). Recently, cancer
therapy could also involve biological therapy or immunotherapy. All of these ches may
pose significant drawbacks for the patient. Surgery, for example, may be contraindicated due to
the health of a patient or may be unacceptable to the patient. Additionally, surgery may not
completely remove neoplastic tissue. Radiation y is only ive when the neoplastic
tissue exhibits a higher sensitiVity to radiation than normal tissue. Radiation therapy can also
often elicit serious side effects. Hormonal therapy is rarely given as a single agent. Although
hormonal y can be effective, it is often used to prevent or delay recurrence of cancer after
other treatments have removed the majority of cancer cells. Certain biological and other
therapies are limited in number and may produce side effects such as rashes or swellings, flu-like
symptoms, including fever, chills and fatigue, digestive tract problems or allergic ons.
With respect to chemotherapy, there are a variety of chemotherapeutic agents available
for treatment of cancer. A number of cancer chemotherapeutics act by inhibiting DNA synthesis,
either directly or indirectly by inhibiting the thesis of deoxyribonucleotide triphosphate
precursors, to prevent DNA replication and concomitant cell division. Gilman et al., Goodman
and Gilman ’s.‘ The Pharmacological Basis of Therapeutics, Tenth Ed. (McGraw Hill, New
York).
Despite bility of a variety of herapeutic agents, chemotherapy has many
drawbacks. Stockdale, Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998.
Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant and often
ous side s including severe nausea, bone marrow depression, and
immunosuppression. Additionally, even with administration of ations of
chemotherapeutic agents, many tumor cells are resistant or develop resistance to the
chemotherapeutic agents. In fact, those cells resistant to the particular chemotherapeutic agents
used in the treatment protocol often prove to be resistant to other drugs, even if those agents act
by different mechanism from those of the drugs used in the c treatment. This phenomenon
is referred to as multidrug resistance. Because of the drug resistance, many s prove
refractory to standard chemotherapeutic treatment protocols.
Other diseases or conditions associated with, or characterized by, red angiogenesis
are also difficult to treat. However, some compounds such as protamine, hepain and steroids
have been proposed to be useful in the treatment of certain specific diseases associated with, or
characterized by, undesired angiogenesis. Taylor et al., Nature 297:307 (1982); Folkman et al.,
Science 221 :719 (1983); and US. Pat. Nos. 5,001,116 and 443. Thalidomide and certain
thalidomide derivatives based on their multiple activities have also been proposed for the
treatment of such es and conditions. US. Patent Nos. 5,593,990, 5,629,327, 5,712,291,
6,071,948 and 6,114,355 to D’Amato.
Still, there is a cant need for safe and effective methods of treating, preventing and
ng cancer and other diseases that are refractory to standard treatments, such as surgery,
radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities
and/or side effects associated with the conventional therapies.
2.6 Methods of Treating Inflammatory Diseases
Current treatments for inflammatory diseases and disorders involve matic
medications and immunosuppressive agents to l symptoms. For example, nonsteroidal
anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, fenoprofen, naproxen, tolmetin,
sulindac, meclofenamate sodium, piroxicam, flurbiprofen, diclofenac, oxaprozin, tone,
etodolac, and ketoprofen have analgesic and anti-inflammatory effects. However, NSAIDs are
(followed by 15A)
In a particular embodiment, ed herein is a method of identifying a drug sensitive cancer patient
in a group of cancer patients comprising:
determining the expression level of cereblon (CRBN) in a biological sample of a cancer,
which has been obtained from a cancer t;
predicting clinical response, monitoring clinical response, or monitoring patient compliance
to dosing by a drug, based on the expression level of CRBN,
wherein the cancer patients are diffuse large B-cell lymphoma patients; and
wherein the drug is thalidomide, lenalidomide, pomalidomide or 3-(5-aminomethyloxo-
nazolinyl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically able
salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
15A (followed by 16)
In another particular embodiment, provided herein is a method of predicting the likelihood of a patient
having e large B-cell lymphoma being responsive to treatment with a drug, comprising:
determining the sion level of cereblon (CRBN) in a biological sample of said diffuse
large B-cell lymphoma, which has been obtained from the patient; and
predicting clinical response, monitoring clinical response, or monitoring patient ance
to dosing by a drug, based on the expression level of CRBN;
wherein the drug is thalidomide, domide, pomalidomide or 3-(5-aminomethyloxo-
4H-quinazolinyl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable
salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
In another particular embodiment, provided herein is a use of a drug selected from thalidomide,
lenalidomide, domide or 3-(5-aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-
dione, a stereoisomer f, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof, in the manufacture of a medicament for the treatment of diffuse large
B-cell ma in a t in need thereof, wherein said patient has a higher expression level of
CRBN in said diffuse large B-cell lymphoma.
In another particular embodiment, ed herein is a use of an anti-CRBN antibody in the
manufacture of a diagnostic agent for predicting clinical response, monitoring al response, or
monitoring patient compliance to dosing by a drug in a cancer patient, based on the expression level
of CRBN, wherein the cancer patients are diffuse large B-cell lymphoma patients; and wherein the
drug is thalidomide, lenalidomide, pomalidomide or 3-(5-aminomethyloxo-4H-quinazolinyl)-
piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, e, hydrate,
co-crystal, clathrate, or polymorph thereof.
patients having a higher response rate to therapy with thalidomide, lenalidomide and/or
pomalidomide, using CRBN levels as a predictive or prognostic factor.
In one embodiment, provided herein is a method of predicting patient response to
treatment of cancer or an inflammatory disease with thalidomide, lenalidomide and/or
domide, the method comprising obtaining biological material from the patient, and
measuring the presence or absence of CRBN.
In one embodiment, the mRNA or protein is purified from the tumor and the ce or
absence of a biomarker is measured by gene or protein expression analysis. In certain
ments, the ce or absence of a biomarker is measured by quantitative real-time PCR
(QRT-PCR), microarray, flow try or immunofluorescence. In other embodiments, the
presence or absence of a biomarker is measured by enzyme-linked immunosorbent based
methodologies (ELISA) or other similar methods known in the art. Biomarkers ated with
non-Hodgkin’s lymphomas are described, for example, in US. Patent Publication No.
2011/0223157, the entirety of which is incorporated by reference in its entirety.
In r embodiment, provided herein is a method of predicting patient response to
treatment in a cancer patient, the method comprising obtaining cancer cells from the patient,
culturing the cells in the presence or absence of a compound provided herein, purifying n
or RNA from the cultured cells, and measuring the ce or absence of a biomarker by ,e.g.,
protein or gene expression analysis. The expression monitored may be, for example, mRNA
expression or protein expression. In one embodiment, the cancer patient is a lymphoma,
leukemia, multiple myeloma, solid tumor, non-Hodgkin’s lymphoma, DLBCL, mantle cell
lymphoma, follicular lymphoma, acute myeloblastic leukemia, chronic cytic leukemia,
MDS or melanoma patient.
In another embodiment, provided herein is a method of monitoring tumor response to
compound (e.g., drug) treatment in a cancer patient. The method comprises obtaining a
biological sample from the patient, measuring the expression of a biomarker in the biological
sample, stering one or more compounds (e.g., drugs) to the patient, thereafter obtaining a
second biological sample from the patient, measuring biomarker sion in the second
biological , and ing the levels of expression, where an increased level of
biomarker expression after treatment indicates the likelihood of an effective tumor response. In
one embodiment, the cancer patient is a lymphoma, leukemia, multiple myeloma, solid tumor,
non-Hodgkin’s lymphoma, DLBCL, mantle cell lymphoma, follicular lymphoma, acute
lastic leukemia, chronic lymphocytic leukemia, MDS or melanoma patient.
In one embodiment, a decreased level of biomarker expression after treatment indicates
the likelihood of effective tumor response. The ker sion monitored can be, for
example, mRNA expression or protein expression. The expression in the treated sample can
increase, for example, by about 1.5X, 2.0X, 3X, 5X, or more. In one embodiment, the tumor is a
lymphoma, leukemia, multiple myeloma, solid tumor, non-Hodgkin’s lymphoma, DLBCL or
melanoma.
In another embodiment, provided herein is a method of ting the sensitivity to
nd (e.g., drug) treatment in a cancer patient, specifically, a le myeloma or non-
Hodgkin’s lymphoma patient (e.g., . The method comprises obtaining a biological
sample from the patient, optionally isolating or ing mRNA from the biological sample,
amplifying the mRNA transcripts by, e.g., RT-PCR, where a higher baseline level of a specific
biomarker indicates a higher likelihood that the cancer will be sensitive to treatment with a
compound (e.g., drug). In certain embodiments, the biomarker is a gene or protein ated
with multiple myeloma or non-Hodgkin’s ma (e.g., DLBCL). In one ment, the
genes are selected from the group consisting of DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-
l, FAS l, RANBP6, DUS3L, PHGDH, AMPK, IRF4 and NFKB.
In one embodiment, identifying a patient having lymphoma, leukemia, multiple myeloma,
solid tumor, non-Hodgkin’s lymphoma, DLBCL, mantle cell lymphoma, follicular lymphoma,
acute myeloblastic leukemia, chronic lymphocytic ia, MDS or melanoma sensitive to
treatment with thalidomide, lenalidomide, pomalidomide and/or 3-(5-aminomethyloxo-4H-
quinazolinyl)-piperidine-2,6-dione, comprises identifying a gene or protein associated with
CRBN. In one embodiment, the gene or protein associated with CRBN is selected from the
group consisting of DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-l, FASl, RANBP6, DUS3L,
PHGDH, AMPK, IRF4 and NFKB.
In one embodiment, identifying a patient having lymphoma, leukemia, le a,
a solid tumor, non-Hodgkin’s lymphoma, DLBCL or melanoma sensitive to treatment with
thalidomide, lenalidomide, pomalidomide and/or 3-(5-aminomethyloxo-4H—quinazolin
yl)-piperidine-2,6-dione comprises measuring the level of CRBN activity in the patient. In
r embodiment, measuring the level of CRBN activity in the patient comprises measuring
DDB l, DDB2, GSK3B, CUL4A, CUL4B, XBP- l, FAS l, RANBP6, DUS3L, PHGDH, AMPK,
IRF4 and/or NFKB in cells obtained from the patient.
In still other ments, ed herein are methods of predicting the sensitivity to
compound (e.g, drug) treatment in a patient having a disease or disorder selected from systemic
lupus erythematosus, ANCA-induced vasculitis, glomerulonephritis, acute r’s
granulomatosis, Myasthenia Gravis, Sjogren Syndrome, anti-phospholipid syndrome, rheumatoid
arthritis and fibrotic conditions such as systemic sclerosis. The method comprises ing a
biological sample from the patient, optionally ing or purifying mRNA from the ical
sample, amplifying the mRNA transcripts by, e.g., RT-PCR, where a higher baseline level of a
specific biomarker indicates a higher likelihood that the disease or disorder will be sensitive to
treatment with a compound (e.g., drug). In certain embodiments, the biomarker is a gene or
n selected from the group consisting of DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-l,
FAS l, RANBP6, DUS3L, PHGDH, AMPK, IRF4 and NFKB.
In one embodiment, identifying a patient having systemic lupus erythematosus, ANCA-
induced vasculitis, glomerulonephritis, acute Wegener’s omatosis, Myasthenia ,
Sjogren Syndrome, anti-phospholipid syndrome, rheumatoid arthritis or systemic sclerosis and
ive to treatment with thalidomide, lenalidomide, pomalidomide and/or 3-(5-amino
methyloxo-4H—quinazolinyl)-piperidine-2,6-dione, ses identifying a gene or protein
associated with CRBN. In one embodiment, the gene or protein ated with CRBN is
selected from the group consisting of DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-l, FAS l,
RANBP6, DUS3L, PHGDH, AMPK, IRF4 and NFKB.
In one embodiment, identifying a patient having systemic lupus erythematosus, ANCA-
induced vasculitis, glomerulonephritis, acute Wegener’s granulomatosis, Myasthenia Gravis,
Sjogren Syndrome, anti-phospholipid syndrome, rheumatoid arthritis or systemic sclerosis
sensitive to treatment with thalidomide, domide, pomalidomide and/or 3-(5-amino
methyloxo-4H—quinazolinyl)-piperidine-2,6-dione comprises measuring the level of CRBN
activity in the patient. In another ment, measuring the level of CRBN activity in the
patient comprises measuring DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-l, FASl, RANBP6,
DUS3L, PHGDH, AMPK, IRF4 and/or NFKB in cells obtained from the patient.
In one embodiment, the compound is thalidomide.
In another embodiment, the compound is lenalidomide.
In another embodiment, the compound is pomalidomide.
In another embodiment, the compound is 3-(5-aminomethyloxo-4H—quinazolin
yl)-piperidine-2,6-dione, or an enantiomer thereof, or a pharmaceutically acceptable salt,
rph, solvate or hydrate thereof.
Also provided herein are kits useful for predicting the likelihood of an effective
ma, leukemia, le myeloma, a solid tumor, non-Hodgkin’s lymphoma, diffilse large
B-cell lymphoma mantle cell lymphoma, follicular lymphoma, acute myeloblastic leukemia,
chronic lymphocytic leukemia, MDS or melanoma treatment or for monitoring the effectiveness
of a treatment with one or more compounds (e.g., . The kit comprises a solid support, and
a means for detecting the protein expression of at least one biomarker in a biological sample.
Such a kit may employ, for example, a dipstick, a membrane, a chip, a disk, a test strip, a , a
microsphere, a slide, a multiwell plate, or an optical fiber. The solid support of the kit can be, for
example, a plastic, silicon, a metal, a resin, glass, a ne, a particle, a precipitate, a gel, a
polymer, a sheet, a , a polysaccharide, a capillary, a film, a plate, or a slide. The biological
sample can be, for example, a cell culture, a cell line, a tissue, an oral tissue, gastrointestinal
tissue, an organ, an lle, a ical fluid, a blood sample, a urine sample, or a skin sample.
The biological sample can be, for example, a lymph node biopsy, a bone marrow biopsy, or a
sample of peripheral blood tumor cells.
In another embodiment, the kit comprises a solid support, nucleic acids ting the
support, where the nucleic acids are complementary to at least 20, 50, 100, 200, 350, or more
bases ofmRNA, and a means for ing the expression of the mRNA in a biological sample.
In n embodiments, the kits provided herein employ means for detecting the
expression of a biomarker by quantitative real-time PCR CR), microarray, flow
cytometry or immunofluorescence. In other embodiments, the expression of the biomarker is
ed by ELISA-based methodologies or other similar methods known in the art.
In still other embodiments, the kits provided herein are useful for predicting the
likelihood of an effective treatment of a disease or disorder selected from systemic lupus
erythematosus, ANCA-induced vasculitis, glomerulonephritis, acute Wegener’s granulomatosis,
Myasthenia Gravis, Sjogren Syndrome, anti-phospholipid syndrome, rheumatoid arthritis and
ic conditions such as systemic sclerosis.
In addition to the methods described above, a compound ed herein is administered
in combination with a therapy conventionally used to treat, prevent or manage a disease or
disorder described herein. Examples of such conventional therapies include, but are not limited
to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and
immunotherapy.
Also provided herein are pharmaceutical compositions, single unit dosage forms, dosing
regimens and kits which comprise a compound provided herein, or a pharmaceutically
acceptable salt, solvate, hydrate, isomer, clathrate, or g thereof, and a , or
onal, active agent. Second active agents include specific combinations, or ails,” of
drugs.
4. BRIEF DESCRIPTION OF THE FIGURES
Figures 1A & lB: Confirmation of CRBN knockdown by siRNAs in H929 and U266
multiple myeloma cells.
Figures 2A — 2C: Knockdown of CRBN abrogated Gl arrest induced by lenalidomide
(“Len”), pomalidomide (“Pom”) and nd B.
Figure 3A: CRBN own in U266Bl cells confirmed by RT-PCR.
Figure 3B: CRBN knockdown abrogates lenalidomide and pomalidomide effect on cell
cycle in U266 cells.
Figures 3C & 3D: Knockdown of CRBN prevents increase of l in lenalidomide
and pomalidomide treated U266 cells as detected by RT-PCR and Western blot analysis.
Figures 4A — 4D: CRBN knockdown abrogates drug effect on phosphorylation ofpr
and IRF-4 in H929 cells.
s 5A — 5C: Cell cycle and gene expression profiles in U266B1 cells transfected
with CRBN-siRNA.
Figures 6A — 6D: DDBl knockdown only partially affected cell cycle delay induced by
lenalidomide and pomalidomide in U266 cells.
Figures 7A & 7B: Lenalidomide and pomalidomide decrease total K48-linked
polyubiquitination but not Klinked tination in H929.
Figure 8: 1 hour up-regulated ubiquitination, no MGl32.
Figure 9: 4 hour up-regulated ubiquitination, no MGl32.
Figure 10: 1 hour up-regulated ubiquitination, MGl32.
Figure 11: 4 hour up-regulated ubiquitination, MGl32.
Figures 12A — 12D: Effect of CRBN knockdown on TNFOL and IL-2 levels in T cells.
Figures 13A — 13C: Effect of CUL4A and CUL4A knockdown on TNFOL and IL-2 levels
in T cells.
Figure 14: Antiproliferative activity of lenalidomide vs. CRBN expression in DLBCL
cells.
Figure 15A: Map of CRBN_034 clone.
Figure 15B: Map of DDB1_004 clone.
Figure 16A: Antiproliferative activity of lenalidomide in CRBN-sensitive myeloma cells.
Figure 16B: oliferative activity of pomalidomide in CRBN-sensitive myeloma
cells.
Figure 16C: Antiproliferative activity of Compound B in CRBN-sensitive myeloma cells.
Figure 17: Peptides regulated by lenalidomide (“Len”) and pomalidomide (“Pom”)
without MGl32 in 1 hour ubiquitination experiments.
Figure 18: Peptides regulated by lenalidomide (“Len”) and pomalidomide (“Pom”) with
MGl32 in 1 hour ubiquitination experiments.
Figure 19: Peptides regulated by lenalidomide ) and pomalidomide )
t MGl32 in 4 hour ubiquitination experiments.
Figure 20: Peptides regulated by lenalidomide (“Len”) and domide (“Pom”) with
MGl32 in 4 hour ubiquitination experiments.
Figure 21: Table of common peptides between domide ) and pomalidomide
(“Pom”) in ubiquitination experiments.
Figure 22: Table of common hits in multiple lenalidomide (“Len”) and pomalidomide
(“Pom”) ubiquitination experiments.
Figure 23: Ubiscan data for lenalidomide (“Len” or “Rev”), pomalidomide (“Pom”), and
Compound B.
Figure 24A: ABC-DLBCL signature genes.
Figure 24B: NF-KB activity and IRF4 ty in DLBCL cells.
Figure 24C: “ABC Scores” ofDLBCL cell lines.
Figure 25: Lenalidomide ts proliferation ofABC-DLBCL cells in vitro.
2012/035429
Figure 26: Lenalidomide ent also induced apoptosis of ive cell lines such as
OCI-Lle.
s 27A - 27C: Effect of Lenalidomide on IRF4 expression in ABC-DLBCL cell
lines.
Figure 28: Mutation analysis of CARDll coiled-coil domain 1 in DLBCL cell lines.
Figures 29A — 29C: Lenalidomide inhibits activation of CARDl l-Bcl-lO-MALTl
complex in sensitive DLBCL cell lines.
Figures 30A - 30C: Lenalidomide inhibits NF-KB activity in BCL cells.
Figures 3 1A — 3 1D: Alteration of IRF4 expression in ABC-DLBCL cells affects cell
sensitivity to lenalidomide.
Figures 32A — 32D: Downregulation of IRF4, NF-KB and eration by lenalidomide
requires the presence of cereblon.
s 33A- 33B: Lenalidomide inhibits tumor growth in mouse xenograft model with
OCI-Lle ABC-DLBCL.
Figures 34A — 34B: “ABC ” and baseline IRF4/CRBN levels correlate
lenalidomide sensitivity of DLBCL cells.
Figure 35: Alignment between heavy chain amino acid sequences of antibodies CGN
l-ll (top; SEQ ID NO:5) and CGN4-5 m; SEQ ID NO:8).
Figures 36: Alignment n light chain amino acid sequences of antibodies CGNl-
ll (top; SEQ ID NO:7) and CGN4-5 (bottom; SEQ ID NO:ll).
Figures 37A & 37B: Confocal immunofluorescent analysis of DF15 (left panel) and
DF15R cells (right panel) using 1 ug/ml CGN4-5 antibody (green) (A) or CGN4-5
antibody / CRBN blocking peptide mix (1 :5 excess ratio) (B). Nuclear staining performed with
Dapi (blue).
Figure 38: Immunoblot with myeloma cells containing endogenous CRBN (DFl5),
DFl5R with no CRBN and HEK293 cells expressing recombinant flag-tagged CRBN.
Figure 39A & 39B: Binding of thalidomide and other compounds to CRBN
. DETAILED DESCRIPTION OF THE INVENTION
The methods provided herein are based, in part, on the discovery that cereblon is
associated with the anti-proliferative activities of certain drugs, such as the compounds provided
herein. In some embodiments, Cereblon (CRBN) may be utilized as a biomarker to indicate the
effectiveness or progress of a disease treatment with a compound provided herein.
Without being bound to a particular theory, CRBN g may contribute to or even be
required for anti-proliferative or other activities of certain compounds, such as the compounds
provided herein. In certain embodiments, the compounds ed herein bind directly to
CRBN-DDBl and/or the CRBN E3 ubiquitin-ligase complex. Mutations in CRBN could be
associated with resistance to the compounds provided herein.
For example, the levels of CRBN were significantly lower in the pomalidomide-resistant
cells line DFlSR and the lenalidomide-resistant cells, H929 RlO-l, H929 RIO-2, H929 RIO-3,
H929 RIO-4 and MMl/R compared to the matched parental lines. Furthermore, an interesting
mutation was found in CRBN gene of one of the myeloma lines that had acquired resistance to
lenalidomide while in the parental line the CRBN gene was wild type. This mutation mapped to
the DDBl binding domain in CRBN. Thus, in certain embodiments, the sensitivity of a cancer
cell, e.g., a myeloma cell, or a t having , to therapy with a nd provided
herein is related to CRBN expression.
In relapsed or tory diffuse large B-cell lymphoma (DLBCL), higher responses were
seen in the activated B-cell-like (ABC) subtype than the germinal center B-cell—like subtype. As
provided herein using DLBCL cell lines, it was shown that lenalidomide treatment preferentially
suppressed proliferation ofABC-DLBCL cells in vitro and d tumor growth in a human
tumor xenograft model, with minimal effect on non-ABC-DLBCL cells. This tumoricidal effect
was associated with downregulation of eron regulatory factor 4 (IRF4), a hallmark ofABC-
DLBCL cells.
IRF4 inhibition by domide caused gulation of B cell receptor (BCR)—
dependent NF-KB activation. While IRF4-specific siRNA mimicked s of lenalidomide
reducing NF-KB activation, IRF4 pression enhanced NF-KB activation and conferred
resistance to lenalidomide. Furthermore, lenalidomide-induced IRF4 downregulation required
the expression of CRBN. Without being bound to a particular theory, these data show that
domide may have direct antitumor activity against DLBCL cells, preferentially ABC-
DLBCL cells, by blocking IRF4 expression and the BCR-NF-KB signaling pathway in a CRBN-
dependent manner.
It has been proposed that CRBN protein functions as a ate receptor for Cul4-E3-
ligase complexes through its interaction with DDB I. As provided herein, whether in viva
tination is associated with drug responses in multiple a cells has been investigated.
In H929 cells, compounds provided herein se total K48-linked iquitination but not
Klinked ubiquitination after 30 minutes treatment. At present, nearly two dozen proteins are
reported to be degraded by a Cul4-DDBl ligase2. Several studies have shown Cul4/DDB1-
dependent ubiquitination of core histones, DNA repair proteins, cell cycle regulators and key
ing pathways molecules. mTORCl signaling requires proteasomal function and the
involvement of CUL4-DDBl ubiquitin E3 ligase. Using CST Ubiscan technology, 162 unique
ubiquitin-peptides were identified which were significantly modulated by the compounds
provided herein after short treatments (I — 4 h). The corresponding proteins participate in
nucleasome and chromatin function, protein-DNA assembly and histone H2A. The relevance of
this early modification in the mode of action of compounds provided herein, and the relationship
with CRBN and CUL4/DDBl activities are under investigation.
Provided herein are methods for the treatment or management of cancer and
inflammatory diseases using CRBN as a predictive or prognostic factor for the compounds
ed herein. In certain embodiments, provided herein are methods for screening or
identifying cancer patients, e.g., lymphoma, ia, multiple myeloma, solid tumor, non-
Hodgkin’s lymphoma, DLBCL, mantle cell ma, follicular lymphoma, acute myeloblastic
leukemia, chronic lymphocytic leukemia, MDS or melanoma patients, for treatment with
thalidomide, lenalidomide and/or pomalidomide, using CRBN levels as a predictive or
stic factor. In some ments, provided herein are methods for selecting patients
having a higher response rate to y with omide, lenalidomide and/or pomalidomide,
using CRBN levels as a predictive or prognostic factor.
In one embodiment, ed herein is a method of predicting patient response to
treatment of cancer or an inflammatory disease with thalidomide, lenalidomide and/or
pomalidomide, the method comprising obtaining ical material from the patient, and
measuring the presence or absence of CRBN.
In one embodiment, the mRNA or protein is purified from the tumor and the presence or
absence of a biomarker is measured by gene or protein expression analysis. In certain
embodiments, the presence or absence of a ker is measured by quantitative real-time PCR
(QRT-PCR), microarray, flow cytometry or immunofluorescence. In other embodiments, the
presence or absence of a biomarker is measured by enzyme-linked sorbent based
methodologies ) or other similar methods known in the art.
In r embodiment, provided herein is a method of predicting the sensitivity to
compound (e.g., drug) treatment in a cancer patient, such as, a multiple myeloma or non-
Hodgkin’s lymphoma patient. The method comprises obtaining a biological sample from the
patient, ally isolating or purifying mRNA from the biological sample, amplifying the
mRNA transcripts by, e.g., RT-PCR, where a higher baseline level of a specific biomarker
indicates a higher likelihood that the cancer will be sensitive to treatment with a compound (e.g.,
drug). In certain embodiments, the biomarker is a gene or protein associated with multiple
myeloma or non-Hodgkin’s lymphoma (e.g., . In one embodiment, the genes are
selected from the group ting of DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-l, FAS l,
, DUS3L, PHGDH, AMPK, IRF4 and NFKB.
In one embodiment, identifying a patient having ma, leukemia, multiple myeloma,
a solid tumor, non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma,
follicular lymphoma, acute myeloblastic leukemia, chronic lymphocytic leukemia, MDS or
melanoma sensitive to treatment with omide, lenalidomide, pomalidomide and/or 3-(5-
2-methyloxo-4H—quinazolinyl)-piperidine-2,6-dione, comprises identifying a gene
or protein ated with CRBN. In one embodiment, the gene or protein associated with
CRBN is selected from the group ting of DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-
l, FAS l, RANBP6, DUS3L, PHGDH, AMPK, IRF4 and NFKB.
In one embodiment, identifying a patient having lymphoma, leukemia, multiple myeloma,
solid tumor, non-Hodgkin’s lymphoma, DLBCL, mantle cell lymphoma, follicular lymphoma,
acute myeloblastic leukemia, chronic lymphocytic leukemia, MDS or melanoma sensitive to
treatment with thalidomide, lenalidomide, pomalidomide and/or 3-(5-aminomethyloxo-4H-
quinazolinyl)-piperidine-2,6-dione comprises measuring the level of CRBN activity in the
patient. In another embodiment, measuring the level of CRBN activity in the patient comprises
measuring DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-l, FASl, RANBP6, DUS3L,
PHGDH, AMPK, IRF4 and/or NFKB in cells obtained from the patient.
In one embodiment, the compound is thalidomide.
In r embodiment, the compound is lenalidomide.
In r embodiment, the compound is pomalidomide.
In another embodiment, the compound is 3-(5-aminomethyloxo-4H—quinazolin
yl)-piperidine-2,6-dione, or an enantiomer thereof, or a pharmaceutically acceptable salt,
polymorph, solvate or hydrate thereof.
In one embodiment, the cancer is multiple myeloma.
In another embodiment, the cancer is non-Hodgkin’s lymphoma. In one embodiment, the
non-Hodgkin’s lymphoma is of the activated B-cell phenotype.
In another embodiment, the cancer is diffuse large B-cell lymphoma. In one embodiment,
the diffuse large B-cell lymphoma is of the ted B-cell phenotype.
In r embodiment, the cancer is mantle cell lymphoma.
In another embodiment, the cancer is follicular lymphoma.
In another embodiment, the cancer is acute myeloblastic ia.
In another embodiment, the cancer is chronic lymphocytic leukemia.
In another embodiment, the cancer is myelodysplastic syndrome.
In another embodiment, the cancer is ma.
In still other embodiments, ed herein are methods of predicting the sensitivity to
compound (e.g, drug) ent in a patient having a disease or disorder selected from systemic
lupus erythematosus, ANCA-induced vasculitis, glomerulonephritis, acute Wegener’s
granulomatosis, Myasthenia Gravis, Sjogren Syndrome, anti-phospholipid syndrome, toid
arthritis and fibrotic conditions such as systemic sclerosis. The method comprises obtaining a
biological sample from the patient, optionally ing or purifying mRNA from the biological
sample, ying the mRNA transcripts by, e.g., RT-PCR, Where a higher baseline level of a
specific biomarker indicates a higher likelihood that the disease or er Will be sensitive to
treatment with a compound (e.g., drug). In certain ments, the biomarker is a gene or
protein selected from the group consisting of DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-l,
FAS l, RANBP6, DUS3L, PHGDH, AMPK, IRF4 and NFKB.
In one embodiment, identifying a patient having selected from systemic lupus
erythematosus, ANCA-induced vasculitis, glomerulonephritis, acute Wegener’s granulomatosis,
Myasthenia Gravis, Sjogren Syndrome, hospholipid syndrome, toid arthritis or
systemic sclerosis sensitive to treatment with thalidomide, lenalidomide, pomalidomide and/or 3-
(5-aminomethyloxo-4H—quinazolinyl)-piperidine-2,6-dione comprises identification of a
gene or protein associated with CRBN. In one embodiment, the gene or protein associated with
CRBN is selected from the group consisting of DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-
l, FAS l, RANBP6, DUS3L, PHGDH, AMPK, IRF4 and NFKB.
In one embodiment, identifying a patient haVing systemic lupus erythematosus, ANCA-
induced vasculitis, glomerulonephritis, acute Wegener’s granulomatosis, Myasthenia Gravis,
Sjogren Syndrome, anti-phospholipid syndrome, rheumatoid arthritis or systemic sclerosis
sensitive to treatment with omide, lenalidomide, domide and/or 3-(5-amino
methyloxo-4H—quinazolinyl)-piperidine-2,6-dione comprises measuring the level of CRBN
actiVity in the patient. In another embodiment, measuring the level of CRBN actiVity in the
patient comprises measuring DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-l, FASl, RANBP6,
DUS3L, PHGDH, AMPK, IRF4 and/or NFKB in cells obtained from the patient.
In one ment, the compound is thalidomide.
In another embodiment, the compound is lenalidomide.
In r embodiment, the compound is domide.
In another embodiment, the compound is 3-(5-aminomethyloxo-4H—quinazolin
yl)-piperidine-2,6-dione, or an enantiomer thereof, or a pharmaceutically acceptable salt,
polymorph, solvate or hydrate thereof.
Also provided herein are kits useful for predicting the likelihood of an effective
lymphoma, leukemia, multiple myeloma, a solid tumor, non-Hodgkin’s lymphoma, diffilse large
B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, acute myeloblastic leukemia,
chronic lymphocytic leukemia, myelodysplastic syndrome or melanoma treatment or for
ring the effectiveness of a treatment with one or more nds (e.g., . The kit
comprises a solid support, and a means for detecting the protein expression of at least one
biomarker in a biological sample. Such a kit may employ, for example, a dipstick, a membrane,
a chip, a disk, a test strip, a filter, a phere, a slide, a multiwell plate, or an l fiber.
The solid support of the kit can be, for example, a plastic, silicon, a metal, a resin, glass, a
membrane, a particle, a precipitate, a gel, a polymer, a sheet, a sphere, a polysaccharide, a
capillary, a film, a plate, or a slide. The biological sample can be, for example, a cell culture, a
cell line, a , an oral tissue, gastrointestinal , an organ, an organelle, a ical fluid,
a blood sample, a urine sample, or a skin sample. The biological sample can be, for example, a
lymph node biopsy, a bone marrow biopsy, or a sample of peripheral blood tumor cells.
In another ment, the kit comprises a solid support, nucleic acids contacting the
support, Where the nucleic acids are complementary to at least 20, 50, 100, 200, 350, or more
bases ofmRNA, and a means for detecting the expression of the mRNA in a biological sample.
In certain embodiments, the kits provided herein employ means for detecting the
sion of a biomarker by quantitative real-time PCR (QRT-PCR), microarray, flow
cytometry or immunofluorescence. In other embodiments, the expression of the biomarker is
measured by ELISA-based methodologies or other similar methods known in the art.
In still other embodiments, the kits provided herein are useful for predicting the
likelihood of an effective treatment of a disease or disorder selected from systemic lupus
erythematosus, ANCA-induced vasculitis, glomerulonephritis, acute Wegener’s granulomatosis,
Myasthenia Gravis, Sjogren Syndrome, anti-phospholipid me, rheumatoid arthritis and
fibrotic conditions such as systemic sclerosis.
Provided herein is a method of selecting a group of cancer patients based on the level of
CRBN sion, or the levels of DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-l, FAS l,
, DUS3L, PHGDH, AMPK, IRF4 or NFKB expression Within the cancer, for the
purposes of ting clinical response, monitoring clinical response, or monitoring t
compliance to dosing by thalidomide, lenalidomide, domide or 3-(5-aminomethyl
—quinazolinyl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically
able salt, solvate, hydrate, co-crystal, ate, or polymorph f; wherein the cancer
patients are selected from multiple myeloma, non-Hodgkin’s lymphoma, diffuse large B-cell
lymphoma, melanoma and solid tumor patients.
In one embodiment, the cancer patients are multiple myeloma patients.
In one embodiment, cancer patients are non-Hodgkin’s lymphoma patients. In one
embodiment, the non-Hodgkin’s lymphoma is of the activated B-cell phenotype.
In one embodiment, cancer patients are e large B-cell lymphoma patients. In one
embodiment, the diffuse large B-cell lymphoma is of the activated B-cell phenotype.
In one embodiment, method of selecting a group of cancer patients is based on the level
of DDBl expression Within the cancer.
In one embodiment, the method of selecting a group of cancer patients is based on the
level of DDB2 sion Within the cancer.
In one embodiment, the method of selecting a group of cancer patients is based on the
level of GSK3B expression within the cancer.
In one embodiment, the method of selecting a group of cancer ts is based on the
level of CUL4A expression within the cancer.
In one embodiment, the method of selecting a group of cancer patients is based on the
level of CUL4B expression within the cancer.
In one embodiment, the method of selecting a group of cancer ts is based on the
level of XBP-l sion within the cancer.
In one embodiment, the method of selecting a group of cancer ts is based on the
level of FASl expression within the cancer.
In one embodiment, the method of selecting a group of cancer patients is based on the
level of RANBP6 expression within the cancer.
In one embodiment, the method of selecting a group of cancer patients is based on the
level of DUS3L expression within the cancer.
In one embodiment, the method of selecting a group of cancer patients is based on the
level of PHGDH expression within the cancer.
In one embodiment, the method of selecting a group of cancer patients is based on the
level ofAMPK expression within the cancer.
In one embodiment, the method of selecting a group of cancer patients is based on the
level of IRF4 expression within the cancer.
In one ment, the method of selecting a group of cancer patients is based on the
level ofNFKB expression within the cancer.
Also provided herein is a method of identifying or monitoring multiple myeloma patient
resistance to omide, lenalidomide, pomalidomide or 3-(5-aminomethyloxo-4H—
olinyl)-piperidine-2,6-dione therapy, based on the presence or appearance of mutations
within a CRBN gene.
In one embodiment, the on with the CRBN gene is a single-nucleotide
polymorphism in the coding region c.745C>CA causing an amino acid change 249D>YD in the
protein within the DDBl binding domain of CRBN.
In another embodiment, provided herein is a method of selecting a group of patients
sive to treatment with thalidomide, lenalidomide, pomalidomide or 3-(5-aminomethyl-
2012/035429
4-oxo-4H—quinazolinyl)-piperidine-2,6-dione, a stereoisomer thereof, or a ceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; based on the level of
CRBN expression, or the levels of DDBl, DDB2, GSK3B, CUL4A, CUL4B, XBP-l, FAS l,
RANBP6, DUS3L, PHGDH, AMPK, IRF4 or NFKB expression within the patient’s T cells, B
cells, or plasma cells, for the purposes of predicting clinical response, monitoring clinical
response, or monitoring patient compliance to dosing by thalidomide, lenalidomide,
domide or 3-(5-aminomethyloxo-4H—quinazolinyl)-piperidine-2,6-dione, a
stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof
Also provided herein is an isolated CRBN antibody, for example, “CRBN70,” as
prepared according to Example 6.20 or 6.21 below. In one embodiment, the dy is a
polyclonal antibody. In another embodiment, the dy is a monoclonal antibody. In some
embodiments, the antibody is a rabbit polyclonal antibody. In other embodiments, the antibody
is a rabbit monoclonal antibody.
In another embodiment, provided herein is an isolated dy which
specifically binds to the epitope having an amino acid sequence EEFHGRTLHDDDC
(SEQ ID: 1). In another ment, the antibody immunospecifically binds to the epitope
having an amino acid ce EEFHGRTLHDDDC (SEQ ID: 1), wherein the peptide is
coupled to e Limpet Hemocyanin (KLH). In one embodiment, the antibody is a
polyclonal dy. In another embodiment, the antibody is a monoclonal antibody. In some
embodiments, the antibody is a rabbit polyclonal antibody. In other embodiments, the antibody
is a rabbit monoclonal antibody. In certain embodiments, the antibody immunospecif1cally binds
peptide 65-76 (SEQ ID NO:1) of human CRBN (SEQ ID NO:12).
In certain embodiments, provided herein is an antibody that immunospecifically binds
CRBN and comprises a heavy chain having the amino acid sequence depicted in SEQ ID NO:5.
In other embodiment, the antibody immunospecif1cally binds CRBN and comprises a light chain
having the amino acid sequence depicted in SEQ ID NO:7. In some embodiments, the antibody
comprises a heavy chain having the amino acid sequence depicted in SEQ ID NO:5 and a light
chain having the amino acid sequence depicted in SEQ ID NO:7. In certain ments, the
antibody immunospecif1cally binds CRBN and comprises a heavy chain having the amino acid
sequence ed in SEQ ID NO:9. In other embodiment, the antibody immunospecifically
binds CRBN and comprises a light chain having the amino acid sequence depicted in SEQ ID
NO: 1 1. In some embodiments, the antibody comprises a heavy chain having the amino acid
sequence depicted in SEQ ID NO:9 and a light chain having the amino acid sequence depicted in
SEQ ID NO:11. In certain embodiments, the antibody immunospecifically binds peptide 65-76
(SEQ ID NO: 1) of human CRBN (SEQ ID NO: 12).
Also provided herein is a method of utilizing a CRBN antibody (e.g., a rabbit polyclonal
or monoclonal antibody CRBN70, or a rabbit polyclonal or monoclonal antibody that binds
peptide 65-76 (SEQ ID NO: 1) of human CRBN (SEQ ID NO: 12) to measure expression levels
of CRBN in patient tumor or host cells, to predict clinical response, monitor clinical response,
monitor patient compliance to dosing, or monitor development of ance to therapy with
thalidomide, lenalidomide, domide, or 3-(5-aminomethyloxo-4H—quinazolinyl)-
piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof. In one embodiment, the CRBN antibody
immunospecifically binds to the epitope having an amino acid sequence EEFHGRTLHDDD
(SEQ ID NO: 1). In an embodiment, the CRBN antibody specifically binds to
EEFHGRTLHDDD (SEQ ID NO: 1), which is coupled to Keyhole Limpet Hemocyanin (KLH).
In one embodiment, the CRBN antibody is a polyclonal antibody, such as a rabbit polyclonal
antibody. In another embodiment, the CRBN antibody is a monoclonal antibody, such as a
rabbit monoclonal antibody.
5.1 Definitions
As used herein, and unless otherwise specified, the terms “treat,3, “treating” and
“treatment” refer to an action that occurs while a patient is ing from the specified cancer,
which reduces the ty of the cancer, or retards or slows the ssion of the cancer.
The term “sensitivity” and “sensitive” when made in reference to treatment with
compound is a relative term which refers to the degree of effectiveness of the compound in
ing or decreasing the ss of a tumor or the disease being treated. For example, the
term ased sensitivity” when used in reference to treatment of a cell or tumor in tion
with a nd refers to an increase of, at least a 5%, or more, in the effectiveness of the tumor
treatment.
As used herein, and unless otherwise specified, the term peutically effective
amount” of a compound is an amount sufficient to provide a eutic benefit in the treatment
or management of a , or to delay or minimize one or more symptoms associated with the
presence of the cancer. A therapeutically ive amount of a compound means an amount of
therapeutic agent, alone or in combination with other therapies, which provides a therapeutic
benefit in the treatment or management of the cancer. The term “therapeutically ive
amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms
or causes of cancer, or enhances the therapeutic efficacy of another therapeutic agent.
As used herein, an “effective patient tumor response” refers to any increase in the
therapeutic benefit to the patient. An “effective patient tumor response” can be, for example, a
%, 10%, 25%, 50%, or 100% decrease in the rate of progress of the tumor. An “effective
patient tumor response” can be, for example, a 5%, 10%, 25%, 50%, or 100% decrease in the
physical ms of a . An “effective patient tumor response” can also be, for e,
a 5%, 10%, 25%, 50%, 100%, 200%, or more increase in the response of the patient, as
ed by any suitable means, such as gene expression, cell counts, assay results, etc.
The term ihood” generally refers to an se in the probability of an event. The
term “likelihood” when used in reference to the effectiveness of a patient tumor response
generally contemplates an increased probability that the rate of tumor progress or tumor cell
growth will decrease. The term ihood” when used in reference to the effectiveness of a
t tumor response can also generally mean the increase of indicators, such as mRNA or
protein expression, that may evidence an increase in the progress in ng the tumor.
The term “predict” generally means to determine or tell in advance. When used to
“predict” the effectiveness of a cancer treatment, for example, the term “predict” can mean that
the likelihood of the outcome of the cancer treatment can be determined at the outset, before the
treatment has begun, or before the treatment period has progressed substantially.
The term or,” as used herein, generally refers to the overseeing, supervision,
regulation, watching, tracking, or surveillance of an activity. For example, the term “monitoring
the effectiveness of a nd” refers to tracking the effectiveness in treating a cancer in a
patient or in a tumor cell culture. Similarly, the “monitoring,” when used in connection with
patient compliance, either individually, or in a clinical trial, refers to the tracking or confirming
that the patient is ly taking a drug being tested as prescribed. The monitoring can be
performed, for example, by following the expression ofmRNA or protein biomarkers.
An improvement in the cancer or cancer-related disease can be characterized as a
te or l response. “Complete response” refers to an absence of clinically detectable
disease with normalization of any previously abnormal radiographic studies, bone marrow, and
cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements. “Partial response”
refers to at least about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in all
measurable tumor burden (z'.e. the number of malignant cells present in the subject, or the
measured bulk of tumor masses or the quantity of abnormal monoclonal protein) in the absence
ofnew lesions. The term “treatment” contemplates both a complete and a partial response.
“Tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether
malignant or benign, and all pre-cancerous and ous cells and tissues. “Neoplastic,” as
used , refers to any form of dysregulated or unregulated cell growth, whether malignant or
benign, resulting in abnormal tissue growth. Thus, “neoplastic cells” e malignant and
benign cells having dysregulated or unregulated cell growth.
The terms “cancer” and rous” refer to or describe the logical condition in
mammals that is typically characterized by unregulated cell growth. Examples of cancer include,
but are not limited to, blood-bome tumors (e.g., multiple a, lymphoma and leukemia),
and solid tumors.
The term “refractory or resistant” refers to a circumstance where patients, even after
intensive treatment, have residual cancer cells (6.g. leukemia or lymphoma cells) in their
lymphatic system, blood and/or blood forming tissues (e.g., marrow).
As used herein the terms "polypeptide" and "protein" as used interchangeably herein,
refer to a polymer of amino acids of three or more amino acids in a serial array, linked through
peptide bonds. The term "polypeptide" includes proteins, protein fragments, protein analogues,
oligopeptides and the like. The term polypeptide as used herein can also refer to a peptide. The
amino acids making up the polypeptide may be naturally derived, or may be synthetic. The
polypeptide can be purified from a ical .
The term “antibody” is used herein in the broadest sense and covers fully assembled
dies, antibody fragments which retain the ability to specifically bind to the antigen (6.g. ,
Fab, F(ab')2, Fv, and other fragments), single chain antibodies, diabodies, dy chimeras,
hybrid antibodies, bispecific antibodies, humanized antibodies, and the like. The term “antibody”
covers both polyclonal and monoclonal antibodies.
The term “antibody” and “immunoglobulin” or “Ig” may be used interchangeably
herein. The terms odies that immunospecifically bind to a CRBN antigen,3, “antibodies
that immunospecifically bind to a CRBN epitope,” “CRBN antibodies,” CRBN antibodies”
and analogous terms are also used interchangeably herein and refer to antibodies and fragments
thereof, that specifically bind to a CRBN polypeptide, such as a CRBN antigen or e (e.g.,
EEFHGRTLHDDD (SEQ ID NO: 1) or e 65-76 human CRBN (SEQ ID NO: 12)). The
antibodies, including both modified antibodies (i.e., antibodies that comprise a d IgG
(e.g., IgGl) constant domain and unmodified antibodies (i.e., antibodies that do not comprise a
modified IgG (e.g., IgGl) constant domain that specifically bind to a CRBN polypeptide. An
antibody or a nt f that immunospecifically binds to a CRBN antigen may be cross-
reactive with related antigens. In certain embodiments, an antibody or a fragment thereof that
immunospecifically binds to a CRBN antigen does not cross-react with other antigens. An
antibody or a fragment thereof that immunospecifically binds to a CRBN antigen can be
identified, for e, by immunoassays, BIAcore, or other techniques known to those of skill
in the art. An antibody or a fragment thereof binds specifically to a CRBN antigen when it binds
to a CRBN antigen with higher affinity than to any cross-reactive antigen as determined using
experimental techniques, such as radioimmunoassays (RIA) and enzyme-linked immunosorbent
assays (ELISAs). Typically a specific or selective reaction will be at least twice background
signal or noise and more typically more than 10 times background. See, e.g., Paul, ed., 1989,
Fundamental Immunology Second Edition, Raven Press, New York at pages 332-336 for a
discussion ing antibody specificity.
Antibodies provided herein include, but are not limited to, synthetic antibodies,
monoclonal antibodies, recombinantly produced antibodies, pecific antibodies (including
bi-specific antibodies), human antibodies, humanized antibodies, chimeric antibodies,
intrabodies, single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), camelized
dies, Fab fragments, F(ab”) fragments, disulfide-linked Fvs (dev), anti-idiotypic (anti-Id)
antibodies, and epitope-binding fragments of any of the above. In particular, antibodies ed
herein include immunoglobulin molecules and logically active portions of
immunoglobulin molecules, i.e., antigen binding domains or molecules that contain an antigen-
binding site that immunospecifically binds to a CRBN n (e.g., one or more
complementarity ining regions (CDRs) of an anti-CRBN antibody). The antibodies
provided herein can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), any class (e.g., IgGl,
IgG2, IgG3, IgG4, IgAl and IgA2), or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin
molecule. In some embodiments, the anti-CRBN antibodies are fially human, such as fully
human monoclonal CRBN antibodies. In certain ments, antibodies provided herein are
IgG dies, or a class (e.g., human IgG1 or IgG4) or subclass thereof.
The term “antigen binding domain,3, ECantigen binding region,3) CEantigen binding
fragment,” and similar terms refer to that portion of an antibody which comprises the amino acid
residues that interact with an antigen and confer on the binding agent its specificity and affinity
for the n (e.g., the CDR). The antigen binding region can be derived from any animal
s, such as rodents (e.g., rabbit, rat or r) and humans. In some embodiments, the
antigen binding region will be of human origin.
The term “constant region” or “constant domain” of an antibody refers to a carboxy
terminal portion of the light and heavy chain which is not ly involved in binding of the
antibody to antigen but exhibits various or function, such as ction with the Fc
receptor. The terms refer to the portion of an globulin molecule having a more
conserved amino acid sequence relative to the other portion of the globulin, the variable
domain, which contains the antigen binding site. The constant domain contains the CH1, CH2
and CH3 s of the heavy chain and the CL domain of the light chain.
The term “epitope” as used herein refers to a localized region on the surface of an antigen,
such as CRBN polypeptide or CRBN polypeptide fragment, that is capable of being bound to one
or more antigen binding regions of an antibody, and that has antigenic or immunogenic activity
in an animal, such as a mammal (e.g., a human), that is capable of eliciting an immune response.
An epitope having immunogenic activity is a portion of a polypeptide that elicits a antibody
response in an animal. An epitope having nic activity is a portion of a polypeptide to
which an antibody immunospecifically binds as determined by any method well known in the art,
for example, by the assays described herein. Antigenic epitopes need not necessarily be
genic. Epitopes usually consist of chemically active surface groupings of molecules
such as amino acids or sugar side chains and have specific three dimensional structural
characteristics as well as specific charge characteristics. A region of a polypeptide contributing
to an e may be contiguous amino acids of the polypeptide or the epitope may come
together from two or more non-contiguous regions of the polypeptide. The epitope may or may
not be a three-dimensional surface feature of the antigen. An exemplary epitope of CRBN
ed herein is EEFHGRTLHDDD (SEQ ID NO: 1) or peptide 65-60 of CRBN (SEQ ID
NO: 1 3).
The terms “fillly human dy” or “human dy” are used interchangeably herein
and refer to an antibody that comprises a human variable region and, in some embodiments, a
human constant region. In specific embodiments, the terms refer to an antibody that comprises a
variable region and constant region of human origin. “Fully human” anti-CRBN antibodies, in
certain embodiments, can also encompass dies which bind CRBN polypeptides and are
encoded by nucleic acid sequences which are naturally occurring somatic ts of human
germline immunoglobulin nucleic acid sequence. In a specific embodiment, the anti-CRBN
dies provided herein are fully human antibodies. The term “fully human dy”
includes antibodies having variable and constant regions corresponding to human germline
immunoglobulin ces as described by Kabat et al., Sequences of Proteins of Immunological
st, Fifth Edition, US. Department of Health and Human Services, NIH Publication No. 91-
3242, 1991. Exemplary methods of producing fially human antibodies are provided, e.g., in the
Examples herein, but any method known in the art may be used.
The phrase “recombinant human antibody” includes human antibodies that are prepared,
expressed, created or isolated by recombinant means, such as antibodies expressed using a
recombinant expression vector transfected into a host cell, antibodies isolated from a
recombinant, combinatorial human antibody library, antibodies isolated from an animal (e.g., a
mouse or cow) that is transgenic and/or transchromosomal for human immunoglobulin genes
(see, e.g., Taylor, L. D. et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared,
expressed, d or isolated by any other means that involves ng of human
immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies
can have variable and constant regions derived from human germline immunoglobulin sequences.
See Kabat, E. A. et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition,
US. Department of Health and Human Services, NIH ation No. 91-3242. In certain
embodiments, r, such recombinant human dies are subjected to in vitro
mutagenesis (or, when an animal transgenic for human Ig sequences is used, in viva somatic
mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant
antibodies are sequences that, while derived from and related to human germline VH and VL
sequences, may not naturally exist within the human antibody ne repertoire in vivo.
The term “heavy chain” when used in reference to an antibody refers to five distinct types,
called alpha (or), delta (5), epsilon (a), gamma (y) and mu (u), based on the amino acid sequence
of the heavy chain constant domain. These distinct types of heavy chains are well known and
give rise to five classes of antibodies, IgA, IgD, IgE, IgG and IgM, respectively, including four
subclasses of IgG, namely IgGl, IgGl, IgG3 and IgG4. In some embodiments the heavy chain is
a human heavy chain.
The terms “Kabat numbering,” and like terms are recognized in the art and refer to a
system of numbering amino acid residues which are more variable (i.e. hypervariable) than other
amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen
binding portion thereof. Kabat et al. (1971) Ann. any Acad. Sci. 190:3 82-391 and, Kabat et al.
(1991) ces of Proteins of Immunological Interest, Fifth Edition, US. Department of
Health and Human es, NIH Publication No. 91-3242. For the heavy chain variable region,
the hypervariable region typically ranges from amino acid positions 31 to 35 for CDRl amino
acid ons 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light
chain variable , the hypervariable region typically ranges from amino acid positions 24 to
34 for CDRl, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for
CDR3. Other numbering s will be readily understood by those skilled in the art.
The term “light chain” when used in reference to an antibody refers to two ct types,
called kappa (K) of lambda (9») based on the amino acid sequence of the constant domains. Light
chain amino acid sequences are well known in the art. In certain embodiments, the light chain is
a human light chain.
The term “monoclonal antibody” refers to an antibody obtained from a population of
homogenous or substantially homogeneous antibodies, and each monoclonal antibody will
typically recognize a single epitope on the antigen. In some embodiments, a lonal
antibody,” as used herein, is an antibody produced by a single hybridoma or other cell, n
the antibody immunospecifically binds to only a CRBN epitope as ined, e.g., by ELISA or
other antigen-binding or competitive binding assay known in the art or in the Examples provided
herein. The term “monoclonal” is not limited to any particular method for making the antibody.
For example, monoclonal antibodies ed herein may be made by the hybridoma method as
WO 49299
described in Kohler et a1.; Nature, 256:495 (1975) or may be ed from phage libraries using
the techniques as bed herein, for example. Other methods for the preparation of clonal cell
lines and of monoclonal antibodies expressed thereby are well known in the art. See, e.g.,
Chapter 11 in: Short Protocols in Molecular Biology, (2002) 5th Ed., Ausube1 et al., eds., John
Wiley and Sons, New York. Other exemplary methods of producing other onal
antibodies are provided in the Examples herein.
“Polyclonal antibodies” as used herein refers to an antibody population generated in an
immunogenic response to a protein having many epitopes and thus includes a variety of different
antibodies directed to the same and to different epitopes within the protein. Methods for
producing polyclonal antibodies are known in the art. See, e.g., Chapter 11 in: Short Protocols in
lar Biology, (2002) 5th Ed., Ausubel et al., eds., John Wiley and Sons, New York.
The terms “cereblon” or and similar terms refers to the polypeptides
(“polypeptides, 3, “peptides” and “proteins” are used interchangeably ) comprising the
amino acid sequence any CRBN, such as a human CRBN n (e.g, human CRBN isoform 1,
GenBank Accession No. NP_0573 86 (SEQ ID NO: 12); or human CRBN isoforms 2, GenBank
Accession No. 166953 (SEQ ID NO: 13), each of which is herein incorporated by
reference in its entirety), and related polypeptides, ing SNP variants thereof. Related
CRBN polypeptides include allelic variants (e.g., SNP variants); splice variants; fragments;
derivatives; substitution, deletion, and insertion variants; fusion polypeptides; and interspecies
homologs, which, in certain embodiments, retain CRBN activity and/or are sufficient to generate
an anti-CRBN immune response.
The term “CRBN antigen” refers to that portion of a CRBN polypeptide to which an
antibody immunospecif1cally binds. A CRBN antigen also refers to an analog or derivative of a
CRBN polypeptide or fragment thereof to which an dy immunospecifically binds. A
localized region on the surface of a CRBN n that is capable of eliciting an immune
response is an CRBN “epitope.” A region of a CRBN polypeptide contributing to an epitope
may be contiguous amino acids of the ptide or the epitope may come together from two or
more non-contiguous regions of the polypeptide. The epitope may or may not be a three-
dimensional surface feature of the antigen. In n embodiments, the CRBN epitope is
EEFHGRTLHDDD (SEQ ID NO: 1) or peptide 65-76 of human CRBN (SEQ ID NO: 12).
WO 49299
The term “variable region” or “variable domain” refers to a portion of the light and heavy
, typically about the amino-terminal 120 to 130 amino acids in the heavy chain and about
100 to 110 amino acids in the light chain, which differ ively in sequence among antibodies
and are used in the binding and specificity of each ular antibody for its particular antigen.
The ility in sequence is concentrated in those regions called complimentarily determining
regions (CDRs) while the more highly conserved regions in the variable domain are called
framework regions (FR). The CDRs of the light and heavy chains are primarily responsible for
the interaction of the antibody with n. Numbering of amino acid positions used herein is
according to the EU Index, as in See Kabat, E. A. et al. (1991) Sequences of Proteins of
Immunological Interest, Fifth n, US. Department of Health and Human Services, NIH
ation No. 91-3242. In some embodiments, the variable region is a human variable region.
The term “expressed” or “expression” as used herein refers to the transcription from a
gene to give an RNA nucleic acid molecule at least complementary in part to a region of one of
the two nucleic acid strands of the gene. The term “expressed” or “expression” as used herein
also refers to the translation from the RNA molecule to give a protein, a polypeptide or a portion
thereof.
An mRNA that is “upregulated” is generally increased upon a given treatment or
condition. An mRNA that is “downregulated” generally refers to a decrease in the level of
expression of the mRNA in response to a given treatment or condition. In some situations, the
mRNA level can remain unchanged upon a given treatment or condition.
An mRNA from a patient sample can be “upregulated” when treated with a drug, as
compared to a non-treated control. This upregulation can be, for example, an increase of about
%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 90%, 100%, 200%, 300%, 500%, 1,000%, 5,000%
or more of the comparative control mRNA level.
Alternatively, an mRNA can be “downregulated”, or expressed at a lower level, in
response to administration of n compounds or other agents. A downregulated mRNA can
be, for e, present at a level of about 99%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%,
%, 10%, 1% or less of the ative control mRNA level.
Similarly, the level of a polypeptide or protein biomarker from a patient sample can be
increased when treated with a drug, as compared to a non-treated control. This increase can be
about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 90%, 100%, 200%, 300%, 500%, 1,000%,
,000% or more of the comparative control protein level.
Alternatively, the level of a protein biomarker can be decreased in response to
administration of certain compounds or other agents. This decrease can be, for example, present
at a level of about 99%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, l% or less of
the comparative control protein level.
The terms “determining”, “measuring”, “evaluating”, “assessing” and “assaying” as used
herein lly refer to any form of measurement, and include determining if an element is
present or not. These terms include both quantitative and/or qualitative determinations.
Assessing may be ve or absolute. “Assessing the presence of” can include determining the
amount of something present, as well as determining r it is present or absent.
The terms ic acid” and “polynucleotide” are used interchangeably herein to
be a polymer of any length composed of nucleotides, e.g., ibonucleotides or
ribonucleotides, or compounds ed synthetically, which can hybridize with naturally
occurring c acids in a sequence specific manner analogous to that of two naturally
occurring nucleic acids, 6.g. , can participate in Watson-Crick base pairing interactions. As used
herein in the context of a polynucleotide sequence, the term “bases” (or “base”) is synonymous
with “nucleotides” (or “nucleotide”), z'.e., the monomer subunit of a polynucleotide. The terms
“nucleoside” and “nucleotide” are intended to include those moieties that contain not only the
known purine and pyrimidine bases, but also other heterocyclic bases that have been modified.
Such modifications include methylated purines or pyrimidines, acylated purines or pyrimidines,
alkylated riboses or other heterocycles. In addition, the terms “nucleoside” and “nucleotide”
include those moieties that contain not only conventional ribose and deoxyribose sugars, but
other sugars as well. Modified nucleosides or nucleotides also include modifications on the
sugar moiety, e.g., n one or more of the hydroxyl groups are replaced with halogen atoms
or aliphatic groups, or are filnctionalized as ethers, amines, or the like. “Analogues” refer to
molecules having ural features that are recognized in the literature as being cs,
tives, having ous structures, or other like terms, and include, for e,
polynucleotides incorporating non-natural nucleotides, nucleotide mimetics such as 2'-modified
nucleosides, peptide nucleic acids, oligomeric nucleoside onates, and any polynucleotide
that has added substituent groups, such as protecting groups or linking moieties.
The term “complementary” refers to specific binding between polynucleotides based on
the sequences of the polynucleotides. As used herein, a first polynucleotide and a second
polynucleotide are complementary if they bind to each other in a hybridization assay under
ent conditions, 6.g. if they produce a given or detectable level of signal in a hybridization
assay. Portions of polynucleotides are complementary to each other if they follow conventional
base-pairing rules, 6.g. A pairs with T (or U) and G pairs with C, although small regions (6.g.
less than about 3 bases) of mismatch, insertion, or d sequence may be present.
“Sequence identity” or “identity” in the context of two nucleic acid sequences refers to
the residues in the two sequences which are the same when d for maximum
correspondence over a specified comparison window, and can take into consideration additions,
deletions and substitutions.
The term “substantial identity” or “homologous” in their s grammatical forms in
the context of polynucleotides lly means that a polynucleotide comprises a sequence that
has a desired identity, for example, at least 60% identity, preferably at least 70% sequence
identity, more preferably at least 80%, still more preferably at least 90% and even more
preferably at least 95%, compared to a reference sequence. Another indication that nucleotide
sequences are substantially identical is if two molecules ize to each other under stringent
conditions.
The terms ted” and “purified” refer to isolation of a substance (such as mRNA,
antibody or protein) such that the substance comprises a substantial portion of the sample in
which it resides, i.e. greater than the nce is typically found in its natural or lated state.
Typically, a substantial portion of the sample comprises, e.g., greater than 1%, greater than 2%,
greater than 5%, greater than 10%, greater than 20%, r than 50%, or more, usually up to
about 90%-100% of the sample. For example, a sample of ed mRNA can lly
comprise at least about 1% total mRNA. Techniques for purifying polynucleotides are well
known in the art and e, for example, gel electrophoresis, ion-exchange chromatography,
affinity chromatography, flow sorting, and sedimentation according to density.
The term “sample” as used herein relates to a material or mixture of materials, typically,
although not necessarily, in fluid form, containing one or more ents of interest.
“Biological sample” as used herein refers to a sample obtained from a biological subject,
including sample of biological tissue or fluid , obtained, reached, or collected in vivo or in
situ. A biological sample also includes samples from a region of a biological subject containing
precancerous or cancer cells or tissues. Such samples can be, but are not limited to, organs,
tissues, fractions and cells isolated from a mammal. Exemplary biological samples include but
are not limited to cell lysate, a cell culture, a cell line, a tissue, oral tissue, gastrointestinal tissue,
an organ, an organelle, a ical fluid, a blood sample, a urine sample, a skin sample, and the
like. Preferred biological samples include but are not limited to whole blood, partially purified
blood, PBMCs, tissue biopsies, and the like.
The term “capture agent,” as used herein, refers to an agent that binds an mRNA or
protein through an interaction that is ient to permit the agent to bind and concentrate the
mRNA or protein from a homogeneous mixture.
The term “probe” as used herein, refers to a capture agent that is directed to a specific
target mRNA ker sequence. Accordingly, each probe of a probe set has a respective
target mRNA biomarker. A probe/target mRNA duplex is a structure formed by hybridizing a
probe to its target mRNA biomarker.
The term “nucleic acid” or nucleotide probe” refers to a nucleic acid capable of
binding to a target nucleic acid of mentary sequence, such as the mRNA biomarkers
ed herein, through one or more types of chemical bonds, usually through complementary
base pairing, usually through hydrogen bond ion. As used , a probe may include
natural (e.g., A, G, C, or T) or modified bases (7-deazaguanosine, inosine, etc.). In addition, the
bases in a probe may be joined by a linkage other than a odiester bond, so long as it does
not interfere with ization. It will be understood by one of skill in the art that probes may
bind target sequences lacking complete complementarity with the probe sequence depending
upon the stringency of the hybridization conditions. The probes are preferably directly labeled
with es, for example, chromophores, ores, chromogens, or indirectly labeled with
biotin to which a streptavidin complex may later bind. By ng for the presence or absence
of the probe, one can detect the presence or absence of a target mRNA biomarker of interest.
The term “stringent assay conditions” refers to conditions that are compatible to produce
binding pairs of nucleic acids, e.g., probes and target mRNAs, of sufficient complementarity to
provide for the desired level of specificity in the assay while being generally incompatible to the
formation of binding pairs between binding members of insufficient complementarity to provide
for the d specificity. The term stringent assay conditions generally refers to the
combination of hybridization and wash conditions.
A “label” or a table moiety” in reference to a nucleic acid, refers to a composition
that, when linked with a nucleic acid, s the nucleic acid detectable, for example, by
oscopic, photochemical, biochemical, immunochemical, or chemical means. ary
labels include, but are not limited to, radioactive isotopes, magnetic beads, metallic beads,
colloidal particles, fluorescent dyes, enzymes, biotin, digoxigenin, haptens, and the like. A
“labeled c acid or oligonucleotide probe” is generally one that is bound, either covalently,
through a linker or a chemical bond, or noncovalently, through ionic bonds, van der Waals ,
ostatic attractions, hydrophobic interactions, or hydrogen bonds, to a label such that the
presence of the nucleic acid or probe can be detected by detecting the presence of the label
bound to the nucleic acid or probe.
The terms “Polymerase chain reaction,” or “PCR,” as used herein generally refers to a
procedure wherein small amounts of a nucleic acid, RNA and/or DNA, are amplified as
described, for e, in US. Pat. No. 4,683,195 to Mullis. Generally, sequence information
from the ends of the region of interest or beyond needs to be available, such that oligonucleotide
primers can be designed; these primers will be identical or similar in sequence to opposite
strands of the te to be amplified. The 5' terminal nucleotides of the two primers may
coincide with the ends of the amplified material. PCR can be used to amplify specific RNA
sequences, specific DNA sequences from total genomic DNA, and cDNA transcribed from total
cellular RNA, bacteriophage or plasmid sequences, etc. See generally Mullis et al., Cold Spring
Harbor Symp. Quant. Biol., 51: 263 (1987); Erlich, ed., PCR Technology, (Stockton Press, NY,
1 989).
The term “cycle number” or “CT” when used herein in reference to PCR s, refers
to the PCR cycle number at which the fluorescence level passes a given set threshold level. The
CT measurement can be used, for example, to approximate levels ofmRNA in an original
sample. The CT measurement is often used in terms of “dCT” or the “difference in the CT”
score, when the CT of one nucleic acid is cted from the CT of another nucleic acid.
As used herein, and unless otherwise indicated, the term “optically pure” means a
composition that ses one optical isomer of a compound and is substantially free of other
isomers of that compound. For example, an optically pure composition of a compound having
one chiral center will be substantially free of the te enantiomer of the compound. An
optically pure composition of a compound having two chiral centers will be substantially free of
other diastereomers of the compound. A typical optically pure compound comprises greater than
about 80% by weight of one enantiomer of the compound and less than about 20% by weight of
other enantiomers of the compound, more preferably greater than about 90% by weight of one
enantiomer of the compound and less than about 10% by weight of the other omers of the
compound, even more preferably greater than about 95% by weight of one enantiomer of the
compound and less than about 5% by weight of the other enantiomers of the compound, more
preferably greater than about 97% by weight of one enantiomer of the compound and less than
about 3% by weight of the other enantiomers of the compound, and most preferably greater than
about 99% by weight of one enantiomer of the nd and less than about 1% by weight of
the other enantiomers of the nd.
As used herein and unless otherwise indicated, the term “pharmaceutically acceptable salt”
asses non-toxic acid and base addition salts of the compound to which the term refers.
Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids
or bases know in the art, which include, for example, hydrochloric acid, hydrobromic acid,
phosphoric acid, ic acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid,
succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid,
phthalic acid, embolic acid, enanthic acid, and the like.
nds that are acidic in nature are capable of forming salts with various
pharmaceutically acceptable bases. The bases that can be used to prepare pharmaceutically
acceptable base on salts of such acidic compounds are those that form non-toxic base
addition salts, z'.e., salts containing pharmacologically acceptable cations such as, but not limited
to, alkali metal or ne earth metal salts and the calcium, magnesium, sodium or potassium
salts in particular. Suitable organic bases include, but are not limited to,
N,N-dibenzylethylenediamine, procaine, choline, diethanolamine, ethylenediamine,
meglumaine (N-methylglucamine), lysine, and procaine.
As used herein and unless otherwise indicated, the term “solvate” means a compound
provided herein or a salt thereof, that further includes a stoichiometric or oichiometric
amount of solvent bound by valent intermolecular forces. Where the solvent is water, the
solvate is a hydrate.
As used herein and unless otherwise indicated, the term “stereomerically pure” means a
composition that comprises one stereoisomer of a compound and is ntially free of other
stereoisomers of that compound. For example, a stereomerically pure composition of a
compound having one chiral center will be substantially free of the opposite enantiomer of the
compound. A stereomerically pure composition of a compound having two chiral centers will be
substantially free of other diastereomers of the compound. A typical stereomerically pure
compound comprises greater than about 80% by weight of one stereoisomer of the compound
and less than about 20% by weight of other stereoisomers of the compound, more preferably
greater than about 90% by weight of one stereoisomer of the compound and less than about 10%
by weight of the other stereoisomers of the compound, even more preferably greater than about
95% by weight of one stereoisomer of the compound and less than about 5% by weight of the
other stereoisomers of the compound, and most preferably greater than about 97% by weight of
one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers
of the compound. As used herein and unless otherwise ted, the term “stereomerically
enriched” means a ition that comprises greater than about 60% by weight of one
stereoisomer of a compound, ably greater than about 70% by weight, more preferably
greater than about 80% by weight of one stereoisomer of a compound. As used herein and
unless otherwise indicated, the term “enantiomerically pure” means a stereomerically pure
composition of a compound having one chiral center. Similarly, the term omerically
enriched" means a stereomerically enriched composition of a compound having one chiral .
As used herein and unless otherwise indicated, the term “co-crystal” means a lline
form that ns more than one compound in a crystal lattice. Co-crystals include crystalline
molecular complexes of two or more non-volatile compounds bound together in a crystal lattice
through non-ionic ctions. As used herein, stals include pharmaceutical cocrystals
wherein the crystalline molecular xes nin a therapeutic compound and one or more
additional non-volatile compound(s) (referred to herein as counter-molecule(s)). A counter-
molecule in a pharmaceutical cocrystal is typically a non-toxic pharmaceutically acceptable
molecule, such as, for example, food additives, preservatives, pharmaceutical ents, or other
APIs. In some embodiments, pharmaceutical cocrystals enhance certain physicochemical
properties of drug products (e.g., lity, dissolution rate, bioavailability and/or stability).
without compromising the al structural integrity of the active pharmaceutical ingredient
(API). See, e.g., Jones et al., “Pharmaceutical Cocrystals: An Emerging Approach to Physical
Property Enhancement,” MRS Bulletin, 2006, 31, 875—879; Trask, “An Overview of
Pharmaceutical Cocrystals as Intellectual Property,” Molecular Pharmaceutics, 2007, 4(3), 301—
309; Schultheiss & Newman, aceutical Cocrystals and Their Physicochemical Properties,’ 3
Crystal Growth & Design, 2009, 9(6), 967; Shan & Zaworotko, “The Role of Cocrystals
in ceutical Science,” Drug Discovery Today, 2008, 13(9/ 10), 440—446; and Vishweshwar
et al., “Pharmaceutical Co-Crystals,” J. Pharm. Sci, 2006, 95(3), 499—516.
A biological marker or “biomarker” is a substance whose detection indicates a particular
biological state, such as, for example, the presence of cancer. In some embodiments, biomarkers
can either be determined individually, or several biomarkers can be measured simultaneously.
In some embodiments, a “biomarker” indicates a change in the level ofmRNA
sion that may correlate with the risk or progression of a disease, or with the susceptibility
of the disease to a given treatment. In some embodiments, the biomarker is a nucleic acid, such
as a mRNA or cDNA.
In additional embodiments, a “biomarker” indicates a change in the level of polypeptide
or protein expression that may correlate with the risk, susceptibility to ent, or ssion
of a disease. In some embodiments, the ker can be a polypeptide or protein, or a fragment
thereof. The relative level of c proteins can be determined by methods known in the art.
For example, antibody based methods, such as an immunoblot, enzyme-linked immunosorbent
assay (ELISA), or other methods can be used.
It should be noted that if there is a discrepancy between a depicted structure and a name
given that structure, the depicted structure is to be accorded more weight. In on, if the
stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold
or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all
stereoisomers of it.
The practice of the embodiments ed herein will employ, unless otherwise indicated,
tional techniques of molecular biology, iology, and immunology, which are within
the skill of those working in the art. Such techniques are explained fully in the literature.
Examples of particularly suitable texts for tation include the following: Sambrook et al.
(1989) Molecular Cloning; A Laboratory Manual (2d ed.); D.N Glover, ed. (1985) DNA Cloning,
s I and II; M.J. Gait, ed. (1984) Oligonucleotide Synthesis; B.D. Hames & SJ . Higgins,
eds. (1984) Nucleic Acid ization; B.D. Hames & S.J. Higgins, eds. (1984) Transcription
and ation; R.I. Freshney, ed. (1986) Animal Cell Culture; Immobilized Cells and Enzymes
(IRL Press, 1986); Immunocbemical Methods in Cell and Molecular Biology mic Press,
London); Scopes (1987) Protein Purification: ples and Practice (2d ed.; Springer Verlag,
NY); and D.M. Weir and C. C. Blackwell, eds. (1986) Handbook ofExperimental Immunology,
Volumes I-IV.
.2 Clincal Trial Endpoints
“Overall survival” is defined as the time from randomization until death from any cause,
and is ed in the intent-to-treat population. Overall al should be evaluated in
randomized controlled studies. Demonstration of a statistically significant improvement in
overall survival can be considered to be clinically significant if the toxicity profile is acceptable,
and has often supported new drug approval.
Several nts are based on cancer assessments. These endpoints include disease free survival
(DFS), ive response rate (ORR), time to progression (TTP), progression-free survival
(PFS), and time-to-treatment failure (TTF). The collection and analysis of data on these time-
dependent endpoints are based on indirect assessments, calculations, and tes (e.g., tumor
measurements).
Generally, “disease free survival” (DFS) is defined as the time from randomization until
recurrence of cancer or death from any cause. Although l survival is a conventional
endpoint for most adjuvant settings, DFS can be an ant endpoint in situations where
survival may be prolonged, making a survival endpoint impractical. DFS can be a surrogate for
clinical benefit or it can provide direct eVidence of clinical benefit. This determination is based
on the magnitude of the effect, its risk-benefit relationship, and the disease setting. The
definition of DFS can be complicated, particularly when deaths are noted without prior cancer
progression documentation. These events can be scored either as disease recurrences or as
censored events. Although all methods for statistical analysis of deaths have some limitations,
considering all deaths (deaths from all causes) as recurrences can minimize bias. DFS can be
overestimated using this definition, especially in patients who die after a long period without
observation. Bias can be introduced if the frequency of long-term follow-up Visits is dissimilar
n the study arms or if dropouts are not random e of toxicity.
“Objective response rate” (ORR) is defined as the proportion of patients with cancer reduction of
a predefined amount and for a minimum time period. Response duration usually is measured
from the time of initial response until nted cancer progression. Generally, the FDA has
defined ORR as the sum of partial ses plus complete responses. When defined in this
manner, OR is a direct measure of drug anticancer activity, which can be evaluated in a single-
arm study. If ble, standardized ia should be used to ascertain response. A variety of
response criteria have been ered appropriate (e.g., RECIST criteria) sse et al., (2000)
J. Natl. Cancer Inst, 92: 205-16). The significance of ORR is assessed by its ude and
duration, and the percentage of complete responses (no detectable evidence of cancer).
“Time to progression” (TTP) and “progression-free survival” (PFS) have served as primary
endpoints for drug approval. TTP is defined as the time from randomization until objective
cancer progression; TTP does not include . PFS is defined as the time fiom randomization
until objective cancer progression or death. Compared with TTP, PFS is the preferred regulatory
endpoint. PFS includes deaths and thus can be a better correlate to overall survival. PFS
assumes patient deaths are randomly related to cancer progression. However, in situations where
the majority of deaths are unrelated to cancer, TTP can be an acceptable nt.
As an endpoint to support drug approval, PFS can reflect cancer growth and be assessed before
the determination of a survival benefit. Its determination is not confounded by uent
therapy. For a given sample size, the magnitude of effect on PFS can be larger than the effect on
overall survival. r, the formal validation of PFS as a surrogate for survival for the many
different malignancies that exist can be difficult. Data are sometimes insufficient to allow a
robust tion of the correlation between effects on survival and PFS. Cancer trials are often
small, and proven survival benefits of existing drugs are generally modest. The role of PFS as an
endpoint to support licensing approval varies in different cancer settings. Whether an
improvement in PPS represents a direct clinical benefit or a surrogate for clinical benefit depends
on the magnitude of the effect and the risk-benefit of the new ent ed to available
therapies.
“Time-to-treatment failure” (TTF) is defined as a composite endpoint measuring time from
ization to discontinuation of treatment for any reason, including disease progression,
treatment toxicity, and death. TTF is not recommended as a regulatory endpoint for drug
approval. TTF does not adequately distinguish efficacy from these additional variables. A
regulatory endpoint should clearly distinguish the efficacy of the drug from toxicity, patient or
physician withdrawal, or patient intolerance.
.3 Second Active Agents
The compounds provided herein may be combined with other pharmacologically active
compounds (“second active agents”) in methods and compositions provided herein. It is
believed that certain combinations work synergistically in the treatment of particular types of
, and certain diseases and conditions associated with or characterized by undesired
angiogenesis and/or inflammation. The compounds ed herein provided herein can also
work to alleviate adverse effects associated with certain second active agents, and some second
active agents can be used to ate adverse effects associated with the compounds provided
herein provided herein.
One or more second active ingredients or agents can be used in the methods and
compositions ed herein with the compounds provided . Second active agents can be
large molecules (e.g., proteins) or small les (e.g, tic nic, organometallic, or
organic molecules).
Examples of large molecule active agents include, but are not limited to, hematopoietic
growth factors, cytokines, and monoclonal and polyclonal antibodies. In n embodiments,
large molecule active agents are biological molecules, such as naturally occurring or artificially
made proteins. Proteins that are particularly useful in this disclosure include proteins that
ate the survival and/or proliferation of hematopoietic precursor cells and immunologically
active poietic cells in vitro or in viva. Others stimulate the division and differentiation of
committed erythroid progenitors in cells in vitro or in viva. Particular proteins include, but are
not limited to: interleukins, such as IL-2 (including recombinant IL-II (“rIL2”) and canarypox
IL-2), IL-10, IL-l2, and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b,
interferon alfa-nl, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b; GM-CF and
GM-CSF; and EPO.
ular proteins that can be used in the methods and compositions of the disclosure
include, but are not d to: tim, which is sold in the United States under the trade
name NEUPOGEN® (Amgen, Thousand Oaks, CA); mostim, which is sold in the United
States under the trade name LEUKINE® (Immunex, Seattle, WA); and recombinant EPO, which
is sold in the United States under the trade name EPGEN® (Amgen, Thousand Oaks, CA).
Recombinant and mutated forms of GM-CSF can be prepared as described in US. Patent
Nos. 5,391,485; 5,393,870; and 5,229,496; the sure of each of which is incorporated herein
by reference in its entirety. Recombinant and mutated forms of G-CSF can be prepared as
bed in US. Patent Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; the disclosure of
each of which is incorporated herein by reference in its entirety.
This sure encompasses the use of native, naturally occurring, and recombinant
proteins. The disclosure further encompasses s and derivatives (e.g., modified forms) of
naturally occurring proteins that exhibit, in viva, at least some of the pharmacological activity of
the proteins upon which they are based. Examples of mutants include, but are not d to,
proteins that have one or more amino acid residues that differ from the corresponding residues in
the naturally occurring forms of the proteins. Also encompassed by the term “mutants” are
proteins that lack carbohydrate moieties normally present in their naturally occurring forms (6.g. ,
cosylated forms). Examples of derivatives include, but are not d to, pegylated
derivatives and fusion proteins, such as proteins formed by fiasing IgGl or IgG3 to the protein or
active portion of the protein of interest. See, e.g., Penichet, ML. and Morrison, S.L., J. l.
Methods 248:91-101 (2001).
Antibodies that can be used in combination with the compound of Formula I provided
herein include monoclonal and polyclonal antibodies. es of antibodies include, but are
not limited to, trastuzumab (HERCEPTIN®), rituximab (RITUXAN®),bevacizumab
(AVASTINTM), umab (OMNITARGTM), tositumomab (BEXXAR®), edrecolomab
EX®), panitumumab and G250. The compound of Formula I provided herein can also
be combined with or used in combination with anti-TNF-u antibodies.
Large molecule active agents may be administered in the form of anti-cancer vaccines.
For e, es that secrete, or cause the secretion of, cytokines such as IL-2, SCF,
CXCl4 (platelet factor 4), G-CSF, and GM-CSF can be used in the s, pharmaceutical
compositions, and kits of the disclosure. See, e.g., Emens, L.A., et al., Curr. Opinion M01. Ther.
3(1):77-84 (2001).
Second active agents that are small molecules can also be used to alleviate adverse effects
associated with the administration of the compound of Formula I provided herein. However, like
some large les, many are believed to be capable of providing a synergistic effect when
administered with (e.g., before, after or simultaneously) the compound of Formula 1. Examples
of small molecule second active agents include, but are not limited to, anti-cancer agents,
antibiotics, immunosuppressive agents, and steroids.
Examples of ancer agents include, but are not limited to: abraxane; ace-l l; aciVicin;
aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin;
ametantrone acetate; amrubicin; amsacrine; anastrozole; anthramycin; asparaginase; asperlin;
azacitidine; azetepa; azotomycin; stat; benzodepa; tamide; rene hydrochloride;
bisnafide dimesylate; bizelesin; cin sulfate; brequinar sodium; imine; busulfan;
omycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; mycin;
cisplatin; bine; crisnatol mesylate; cyclophosphamide; bine; dacarbazine;
dactinomycin; daunorubicin hloride; decitabine; dexormaplatin; dezaguanine;
dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;
droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;
eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin
hydrochloride; erbulozole; icin hydrochloride; estramustine; ustine phosphate
sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate; racil; flurocitabine;
fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; herceptin; hydroxyurea;
idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride;
lanreotide acetate; lapatinib; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol
sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; rethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;
methotrexate; methotrexate sodium; metoprine; depa; mitindomide; mitocarcin;
omin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;
mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase;
peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; lfan;
piroxantrone hloride; plicamycin; tane; porfimer sodium; porfiromycin;
prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
ine; psin; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate
sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; stem cell
treatments such as PDA-OOl; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan
WO 49299 2012/035429
sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; fene citrate;
trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin;
tubulozole hydrochloride; uracil mustard; a; vapreotide; verteporfm; vinblastine sulfate;
vincristine sulfate; vindesine; vindesine e; vinepidine e; vinglycinate sulfate;
vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole;
zeniplatin; zinostatin; and zorubicin hydrochloride.
Other anti-cancer drugs e, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3;
-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; eukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;
amrubicin; amsacrine; anagrelide; ozole; andrographolide; angiogenesis inhibitors;
antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,
prostatic carcinoma; antiestrogen; antineoplaston; nse oligonucleotides; aphidicolin
glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; rine; atamestane; atrimustine; axinastatin l; axinastatin 2; axinastatin
3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCIVABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine;
betaclamycin B; betulinic acid; b-FGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; imine; tane; buthionine sulfoximine;
calcipotriol; calphostin C; thecin derivatives; capecitabine; carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein
kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline
sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole;
collismycin A; mycin B; combretastatin A4; combretastatin analogue; conagenin;
crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;
cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;
dexifosfamide; dexrazoxane; apamil; diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-S-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;
nol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; mycin SA;
ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin;
epristeride; estramustine analogue; estrogen agonists; estrogen nists; etanidazole;
etoposide phosphate; tane; fadrozole; fazarabine; fenretinide; filgrastim; f1nasteride;
ridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;
formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine;
ganirelix; nase inhibitors; gemcitabine; glutathione tors; hepsulfam; heregulin;
hexamethylene bisacetamide; hypericin; ibandronic acid; icin; idoxifene; idramantone;
ilmofosine; ilomastat; imatinib (e.g., GLEEVEC®), mod; immunostimulant peptides;
insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; eukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; ct; adine; isobengazole;
isohomohalicondrin B; itasetron; j asplakinolide; kahalalide F; lamellarin-N triacetate; tide;
leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor;
leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;
linear polyamine analogue; lipophilic disaccharide peptide; ilic platinum nds;
lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; loxoribine;
lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;
marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;
menogaril; merbarone; lin; methioninase; metoclopramide; MIF inhibitor; mifepristone;
miltefosine; mirimostim; azone; ctol; mitomycin analogues; mitonaf1de; xin
last growth factor-saporin; mitoxantrone; mofarotene; molgramostim;Erbitux, human
chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol;
mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; orone;
N—acetyldinaline; N—substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine;
napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide;
nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen
(GENASENSE®); 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;
ondansetron; ondansetron; ; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;
oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel tives; palauamine;
palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron;
perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator
inhibitor; platinum complex; platinum compounds; platinum-triamine x; porf1mer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome tors; protein
A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;
pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;
raltitrexed; ramosetron; ras famesyl protein transferase tors; ras inhibitors; ras-GAP
tor; retelliptine demethylated; rhenium Re 186 etidronate; in; ribozymes; RII
retinamide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; saf1ngol; saintopin;
SarCNU; sarcophytol A; sargramostim; Sdi l mimetics; ine; senescence derived inhibitor
1; sense oligonucleotides; signal transduction tors; sizofiran; sobuzoxane; sodium
borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic
acid; spicamycin D; spiromustine; splenopentin; spongistatin l; squalamine; stipiamide;
stromelysin inhibitors; osine; superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan
sodium; tegafilr; tellurapyrylium; telomerase tors; temoporfin; teniposide;
tetrachlorodecaoxide; tetrazomine; lastine; thiocoraline; opoietin; thrombopoietin
mimetic; thymalfasin; oietin receptor agonist; thymotrinan; thyroid stimulating hormone;
tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; translation
inhibitors; tretinoin; triacetyluridine; triciribine; rexate; triptorelin; tropisetron; eride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived
growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; velaresol;
veramine; verdins; verteporfin; lbine; Vinxaltine; Vitaxin; vorozole; zanoterone; zeniplatin;
zilascorb; and zinostatin stimalamer.
Specific second active agents include, but are not limited to, oblimersen
(GENASENSE®), remicade, docetaxel, celecoxib, lan, dexamethasone RON®),
steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar,
carboplatin, bazine, gliadel, tamoxifen, topotecan, rexate, , taxol, taxotere,
fluorouracil, leucovorin, irinotecan, xeloda, CPT-l l, interferon alpha, pegylated interferon alpha
(e.g., PEG INTRON—A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal
daunorubicin, cytarabine, doxetaxol, pacilitaxel, Vinblastine, IL-2, GM-CSF, dacarbazine,
Vinorelbine, zoledronic acid, palmitronate, , busulphan, prednisone, bisphosphonate,
2012/035429
arsenic trioxide, vincristine, doxorubicin ®), paclitaxel, lovir, adriamycin,
estramustine sodium phosphate (EMCYT®), sulindac, and etoposide.
.4 Methods of ent and Prevention
In one embodiment, provided herein is a method of treating and preventing cancer, which
comprises administering to a patient a compound provided herein, or an enantiomer or a mixture
of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or rph thereof.
In another embodiment, provided herein is method of ng cancer, which comprises
administering to a patient a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof
Also provided herein are methods of treating patients who have been previously treated for
cancer but are non-responsive to standard therapies, as well as those who have not previously
been treated. The invention also encompasses methods of treating patients regardless of patient’s
age, although some diseases or disorders are more common in certain age groups. The invention
further encompasses methods of treating patients who have one surgery in an attempt to
treat the disease or condition at issue, as well as those who have not. Because patients with
cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment
given to a patient may vary, depending on his/her prognosis. The skilled clinician will be able to
y determine t undue mentation specific secondary agents, types of surgery,
and types of non-drug based standard y that can be effectively used to treat an individual
patient with cancer.
In yet another embodiment, provided herein is a method of treating, managing, or
preventing diseases and disorders other than cancer that are associated with or characterized by
undesired angiogenesis, which comprises administering to a patient a compound provided herein,
or an enantiomer or a mixture of enantiomers f, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
As used herein, the term r” es, but is not limited to, solid tumors and blood
born tumors. The term “cancer” refers to disease of skin tissues, organs, blood, and vessels,
including, but not limited to, s of the bladder, bone, blood, brain, breast, cervix, chest,
colon, etrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck,
WO 49299
ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus. Specific cancers include,
but are not limited to, advanced ancy, amyloidosis, neuroblastoma, meningioma,
hemangiopericytoma, le brain metastase, glioblastoma orms, glioblastoma, brain
stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant
giolma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal
arcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic
hepatocellular carcinoma, ’s sarcoma, karotype acute myeloblastic leukemia, Hodgkin’s
lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell
lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, malignant
melanoma, ant mesothelioma, ant pleural effusion mesothelioma syndrome,
peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue a,
scleroderma, cutaneous vasculitis, Langerhans cell cytosis, leiomyosarcoma, fibrodysplasia
ans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma,
unrescectable hepatocellular carcinoma, Waldenstrom’s macroglobulinemia, smoldering
myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer,
androgen dependent stage IV non-metastatic te cancer, hormone-insensitive prostate
cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid
carcinoma, medullary thyroid carcinoma, and leiomyoma
In n embodiments, the cancer is a blood borne tumor. In n embodiments, the
blood borne tumor is metastatic. In certain embodiments, the blood borne tumor is drug resistant.
In certain embodiments, the cancer is myeloma or lymphoma.
In certain embodiments, the cancer is a solid tumor. In n embodiments, the solid
tumor is metastatic. In certain embodiments, the solid tumor is drug-resistant. In certain
embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, ovarian cancer, or
glioblastoma.
As used herein to refer to diseases and conditions other than cancer, the terms “diseases
or disorders associated with or terized by undesired angiogenesis,” “diseases or ers
ated with red angiogenesis,” and “diseases or disorders characterized by undesired
angiogenesis” refer to diseases, disorders, and conditions that are caused, mediated, or attended
by undesired, unwanted, or uncontrolled angiogenesis, including, but not limited to,
inflammatory diseases, autoimmune diseases, genetic diseases, allergic diseases, bacterial
diseases, ocular neovascular diseases, choroidal neovascular diseases, and retina neovascular
diseases.
Examples of such diseases or disorders ated with undesired angiogenesis include,
but are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection,
neovascular glaucoma, ental f1broplasia, proliferative retinopathy, trachoma, myopia,
optic pits, epidemnic conjunctivitis, atopic keratitis, superior limbic keratitis, pterygium
keratitis sicca, sjogrens, acne rosacea, phylectenulosis, syphilis, lipid degeneration, bacterial
ulcer, fungal ulcer, Herpes simplex infection, Herpes zoster infection, protozoan infection,
Kaposi sarcoma, Mooren ulcer, Terrien’s marginal degeneration, mariginal keratolysis,
rheumatoid arthritis, ic lupus, polyarteritis, trauma, Wegeners sarcoidosis, Scleritis,
Steven’s Johnson disease, periphigoid radial keratotomy, sickle cell anemia, sarcoid,
xanthoma elasticum, Pagets disease, vein occlusion, artery occlusion, carotid obstructive
disease, chronic uveitis, chronic is, Lyme’s disease, Eales disease, Behcet’s disease, retinitis,
choroiditis, presumed ocular histoplasmosis, Bests disease, rts disease, pars planitis,
chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, rubeosis, sarcodisis,
sclerosis, soriatis, psoriasis, primary sclerosing gitis, proctitis, primary biliary srosis,
idiopathic pulmonary fibrosis, and alcoholic hepatitis.
In certain ments, a therapeutically or prophylactically effective amount of the
compound is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per
day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from
about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to
about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg
per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about
0.02 to about 25 mg per day, or from about 0.05 to about 10 mg per day.
In certain embodiments, the therapeutically or lactically effective amount is about
1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about
50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day.
In one ment, the recommended daily dose range of the compound for the conditions
described herein lie Within the range of from about 0.5 mg to about 50 mg per day, preferably
given as a single once-a-day dose, or in divided doses throughout a day. In some embodiments,
the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage
WO 49299
ranges from about 0.5 to about 5 mg per day. Specific doses per day include 0.5, 1, 1.5, 2, 2.5, 3,
3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day. In other
embodiments, specific doses per day include 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4 mg per day.
In a specific embodiment, the recommended starting dosage may be 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5,
, 15, 20, 25 or 50 mg per day. In another embodiment, the recommended starting dosage may
be 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4 mg per day. The dose may be ted to 15, 20, 25, 30, 35, 40,
45 and 50 mg/day. In a specific embodiment, the compound can be administered in an amount
of about 25 mg/day to patients with cacner. In a particular embodiment, the compound can be
administered in an amount of about 10 mg/day to patients with cancer.
In n embodiments, the therapeutically or prophylactically effective amount is from
about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to
about 25 mg/kg/day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9
mg/kg/day, 0.01 to about 8 day, from about 0.01 to about 7 mg/kg/day, from about 0.01 to
about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day,
from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 mg/kg/day, or from about 0.01
to about 1 mg/kg/day.
The administered dose can also be expressed in units other than day. For example,
doses for parenteral administration can be expressed as mg/mz/day. One of ordinary skill in the
art would readily know how to t doses from mg/kg/day to mg/mz/day to given either the
height or weight of a subject or both (see, www.fda.gov/cder/cancer/animalframe.htm). For
example, a dose of 1 mg/kg/day for a 65 kg human is approximately equal to 38 mg/mZ/day.
In certain embodiments, the amount of the nd administered is sufficient to
provide a plasma concentration of the compound at steady state, ranging from about 0.001 to
about 500 uM, about 0.002 to about 200 uM, about 0.005 to about 100 uM, about 0.01 to about
50 uM, from about 1 to about 50 uM, about 0.02 to about 25 uM, from about 0.05 to about 20
uM, from about 0.1 to about 20 uM, from about 0.5 to about 20 uM, or from about 1 to about 20
In other embodiments, the amount of the compound administered is sufficient to provide
a plasma concentration of the compound at steady state, ranging from about 5 to about 100 nM,
about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to
about 100 nM.
As used , the term “plasma concentration at steady state” is the concentration
reached after a period of administration of a compound provided herein, e.g., the compound of
Formula I, or an enantiomer or a mixture of omers thereof, or a ceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Once steady state is
d, there are minor peaks and troughs on the time dependent curve of the plasma
concentration of the compound.
In certain embodiments, the amount of the compound administered is ient to
provide a maximum plasma concentration (peak concentration) of the compound, ranging from
about 0.001 to about 500 uM, about 0.002 to about 200 uM, about 0.005 to about 100 uM, about
0.01 to about 50 uM, from about 1 to about 50 uM, about 0.02 to about 25 uM, from about 0.05
to about 20 uM, from about 0.1 to about 20 uM, from about 0.5 to about 20 uM,or from about 1
to about 20 uM.
In certain embodiments, the amount of the compound administered is sufficient to
provide a minimum plasma concentration h concentration) of the compound, ranging from
about 0.001 to about 500 uM, about 0.002 to about 200 uM, about 0.005 to about 100 uM, about
0.01 to about 50 uM, from about 1 to about 50 uM, about 0.01 to about 25 uM, from about 0.01
to about 20 uM, from about 0.02 to about 20 uM, from about 0.02 to about 20 uM, or from
about 0.01 to about 20 uM.
In certain embodiments, the amount of the compound administered is sufficient to
provide an area under the curve (AUC) of the compound, ranging from about 100 to about
100,000 ng*hr/mL, from about 1,000 to about 50,000 ng*hr/mL, from about 5,000 to about
,000 ng*hr/mL, or from about 5,000 to about 10,000 ng*hr/mL.
In certain embodiments, the t to be treated with one of the methods provided herein
has not been treated with anticancer therapy prior to the administration of the drug. In certain
embodiments, the patient to be treated with one of the methods provided herein has been treated
with ncer therapy prior to the administration of the drug. In n embodiments, the
patient to be treated with one of the methods provided herein has developed drug resistance to
the anticancer therapy.
The methods provided herein encompass treating a t regardless of t’s age,
although some diseases or disorders are more common in certain age groups. Further provided
herein is a method for treating a t who has undergone surgery in an attempt to treat the
disease or ion at issue, as well in one who has not. Because the subjects with cancer have
heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a
particular subject may vary, ing on his/her prognosis. The skilled ian will be able to
y determine without undue experimentation, specific secondary agents, types of surgery,
and types of non-drug based standard therapy that can be effectively used to treat an individual
subject with cancer.
Depending on the disease to be treated and the subject’s condition, the compound
ed herein, or an enantiomer or a e of enantiomers thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, may be administered
by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection
or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or
topical (e.g., transdermal or local) routes of administration. The compound, or an enantiomer or
a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, e, co-
crystal, clathrate, or polymorph thereof, may be formulated, alone or together, in suitable dosage
unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate
for each route of administration.
In one embodiment, the compound provided herein, or an enantiomer or a mixture of
enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered orally. In another embodiment, the compound, or an
enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or rph thereof, is administered parenterally. In yet r
embodiment, the compound, or an enantiomer or a mixture of omers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof, is
administered intravenously.
The compound, or an enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically able salt, solvate, hydrate, co-crystal, ate, or polymorph thereof,
can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or
over time, such as, e.g., continuous infusion over time or divided bolus doses over time. The
WO 49299
compound can be administered repeatedly if necessary, for example, until the patient experiences
stable disease or regression, or until the patient experiences disease progression or unacceptable
toxicity. For example, stable disease for solid tumors generally means that the perpendicular
diameter of measurable lesions has not increased by 25% or more from the last measurement.
Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal oft/w National
Cancer Institute 92(3): 205-216 (2000). Stable disease or lack f is determined by methods
known in the art such as tion of patient symptoms, physical examination, visualization of
the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly
accepted evaluation modalities.
The compound, or an omer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof,
can be administered once daily (QD), or d into multiple daily doses such as twice daily
(BID), three times daily (TID), and four times daily (QID). In addition, the administration can
be continuous (z'.e., daily for utive days or every day), intermittent, e.g., in cycles (z'.e.,
including days, weeks, or months of rest without drug). As used herein, the term “daily” is
intended to mean that a therapeutic compound is administered once or more than once each day,
for example, for a period of time. The term “continuous” is intended to mean that a therapeutic
compound is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The
term mittent” or “intermittently” as used herein is intended to mean stopping and ng at
either r or lar intervals. For example, intermittent administration of a compound is
administration for one to six days per week, administration in cycles (e.g., daily administration
for two to eight consecutive weeks, then a rest period with no administration for up to one week),
or administration on alternate days. The term ng” as used herein is intended to mean that a
therapeutic compound is administered daily or continuously but with a rest period.
In some embodiments, the frequency of stration is in the range of about a daily
dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day,
three times a day, four times a day, once every other day, twice a week, once every week, once
every two weeks, once every three weeks, or once every four weeks. In one embodiment, the
compound, or an enantiomer or a mixture of omers thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once
a day. In another ment, the compound, or an enantiomer or a mixture of enantiomers
thereof; or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or
polymorph thereof, is administered twice a day. In yet another embodiment, the compound, or
an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or rph thereof, is administered three times a day. In still
another embodiment, the compound, or an enantiomer or a mixture of omers thereof; or a
pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is
administered four times a day.
In n embodiments, the compound, or an enantiomer or a mixture of enantiomers
thereof; or a ceutically able salt, solvate, hydrate, co-crystal, clathrate, or
polymorph thereof, is administered once per day from one day to six months, from one week to
three months, from one week to four weeks, from one week to three weeks, or from one week to
two weeks. In certain embodiments, the nd, or a pharmaceutically acceptable salt or
e thereof, is administered once per day for one week, two weeks, three weeks, or four
weeks. In one embodiment, the compound, or an enantiomer or a mixture of omers thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph
thereof, is administered once per day for one week. In another embodiment, the compound, or
an enantiomer or a e of enantiomers thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, co-crystal, clathrate, or polymorph thereof, is administered once per day for two weeks.
In yet another embodiment, the compound, or an enantiomer or a mixture of enantiomers thereof;
or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph
thereof, is stered once per day for three weeks. In still another embodiment, the
compound, or an enantiomer or a mixture of omers thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once
per day for four weeks.
5.5 Combination Therapy With A Second Active Agent
A compound ed herein, or an enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof,
can also be combined or used in combination with other therapeutic agents useful in the
treatment and/or prevention of a disease described herein.
In one embodiment, provided herein is a method of treating, preventing, or managing
cancer, comprising administering to a patient compound provided herein, or an enantiomer or a
mixture of enantiomers thereof; or a pharmaceutically able salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof; in combination with one or more second active agents, and
optionally in combination with radiation therapy, blood transfilsions, or surgery. Examples of
second active agents are disclosed herein (see, e.g., section 5.3).
As used herein, the term “in combination” includes the use of more than one therapy (e.g.
one or more prophylactic and/or therapeutic agents). However, the use of the term “in
combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic
agents) are administered to a patient with a disease or disorder. A first therapy (e. g., a
prophylactic or therapeutic agent such as a compound provided herein, a compound ed
herein, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically able
salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof) can be stered prior to
(e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours,
24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8
weeks, or 12 weeks before), concomitantly with, or subsequent to (e. g., 5 minutes, 15 minutes,
30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours,
96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the
administration of a second therapy (e.g., a lactic or therapeutic agent) to the subject.
Triple therapy is also contemplated herein.
Administration of the compound and one or more second active agents to a patient can
occur simultaneously or tially by the same or different routes of administration. The
suitability of a particular route of administration employed for a particular active agent will
depend on the active agent itself (e.g., whether it can be administered orally t
decomposing prior to entering the blood stream) and the cancer being d.
The route of administration of the compound is independent of the route of
administration of a second therapy. In one embodiment, the compound is administered orally.
In another embodiment, the compound is administered intravenously. Thus, in ance with
these embodiments, the compound is administered orally or intravenously, and the second
therapy can be administered , parenterally, intraperitoneally, intravenously, intraarterially,
transdermally, sublingually, intramuscularly, rectally, transbuccally, asally, liposomally,
Via tion, vaginally, intraoccularly, Via local delivery by er or stent, subcutaneously,
intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one
embodiment, the compound and a second therapy are administered by the same mode of
administration, orally or by IV. In another embodiment, the compound is administered by one
mode of administration, e.g., by IV, whereas the second agent (an anticancer agent) is
administered by another mode of administration, e.g., orally.
In one embodiment, the second active agent is administered intravenously or
subcutaneously and once or twice daily in an amount of fiom about 1 to about 1000 mg, from
about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg.
The specific amount of the second active agent will depend on the specific agent used, the type
of disease being treated or managed, the severity and stage of disease, and the amount of the
drug provided herein and any optional additional active agents rently administered to the
patient. In certain ments, the second active agent is oblimersen ENSE®), GM-
CSF, G-CSF, SCF, EPO, taxotere, irinotecan, azine, transretinoic acid, topotecan,
pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2,
1L8, IL18, IFN, Ara-C, vinorelbine, or a combination thereof.
In certain ments, GM-CSF, G-CSF, SCF or EPO is administered subcutaneously
during about five days in a four or six week cycle in an amount ranging from about 1 to about
750 mg/mZ/day, from about 25 to about 500 mg/mZ/day, from about 50 to about 250 mg/mZ/day,
or from about 50 to about 200 mg/mz/day. In certain embodiments, GM-CSF may be
administered in an amount of fiom about 60 to about 500 mcg/m2 intravenously over 2 hours or
from about 5 to about 12 mcg/mZ/day subcutaneously. In certain embodiments, G-CSF may be
administered subcutaneously in an amount of about 1 mcg/kg/day initially and can be adjusted
depending on rise of total granulocyte . The nance dose of G-CSF may be
administered in an amount of about 300 (in smaller patients) or 480 mcg subcutaneously. In
certain embodiments, EPO may be administered aneously in an amount of 10,000 Unit 3
times per week.
In certain embodiments, a compound ed herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate,
or polymorph thereof, is administered with melphalan and dexamethasone to patients with
amyloidosis. In certain ments, a compound provided herein, e.g., the nd of
Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and steroids can be
administered to patients with amyloidosis.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph f, is administered with gemcitabine and cisplatinum to ts with locally
advanced or metastatic transitional cell bladder cancer.
In certain ments, a compound ed herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered in combination with a second active ingredient as follows:
temozolomide to pediatric patients with relapsed or progressive brain tumors or recurrent
neuroblastoma; celecoxib, etoposide and cyclophosphamide for relapsed or progressive CNS
; temodar to ts with recurrent or progressive meningioma, malignant meningioma,
iopericytoma, multiple brain metastases, sed brain tumors, or newly diagnosed
glioblastoma multiforms; ecan to patients with recurrent glioblastoma; carboplatin to
pediatric patients with brain stem glioma; procarbazine to pediatric patients with progressive
malignant gliomas; cyclophosphamide to patients with poor prognosis malignant brain tumors,
newly diagnosed or recurrent glioblastoma multiforms; Gliadel® for high grade recurrent
malignant gliomas; temozolomide and fen for anaplastic astrocytoma; or topotecan for
gliomas, glioblastoma, anaplastic astrocytoma or anaplastic oligodendroglioma.
In certain embodiments, a compound provided herein, or an enantiomer or a e of
omers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered with methotrexate, cyclophosphamide, taxane, abraxane,
lapatinib, herceptin, aromatase inhibitors, selective estrogen modulators, en receptor
antagonists, and/or PLX3397 (Plexxikon) to patients with metastatic breast cancer.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers f, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, ate,
or polymorph thereof, is administered with temozolomide to patients with neuroendocrine
tumors.
In certain embodiments, a compound provided , or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered with gemcitabine to patients with recurrent or metastatic
head or neck cancer.
In certain embodiments, a nd provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered with gemcitabine to patients with pancreatic cancer.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered to patients with colon cancer in combination with ARISA®,
avastatin, taxol, and/or re.
In certain embodiments, a nd provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate,
or polymorph thereof, is administered with capecitabine and/or PLX4032 (Plexxikon) to patients
with refractory colorectal cancer or patients who fail first line therapy or have poor performance
in colon or rectal arcinoma.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered in combination with fluorouracil, leucovorin, and
irinotecan to patients with Dukes C & D colorectal cancer or to patients who have been
previously treated for metastatic colorectal cancer.
In certain embodiments, a compound ed herein, or an omer or a e of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered to patients with refractory colorectal cancer in
combination with capecitabine, xeloda, and/or CPT-l 1.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate,
or polymorph f, is administered with capecitabine and ecan to patients with refractory
ctal cancer or to patients with unresectable or metastatic colorectal carcinoma.
In certain ments, a compound provided herein, or an enantiomer or a mixture of
enantiomers f, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate,
or rph thereof, is stered alone or in combination with interferon alpha or
capecitabine to patients with unresectable or metastatic hepatocellular carcinoma; or with
cisplatin and thiotepa to patients with primary or atic liver cancer.
In certain ments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate,
or polymorph thereof, is administered in combination with pegylated interferon alpha to patients
with Kaposi’s sarcoma.
In certain embodiments, a compound ed herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered in combination with fludarabine, carboplatin, and/or
topotecan to patients with refractory or relapsed or high-risk acuted myelogenous leukemia.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, ate,
or polymorph thereof, is administered in ation with liposomal daunorubicin, topotecan
and/or cytarabine to patients with unfavorable karotype acute myeloblastic leukemia.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers f, or a pharmaceutically acceptable salt, e, e, co-crystal, ate,
or polymorph thereof, is administered in combination with gemcitabine, abraxane, erlotinib,
geftinib, and/or irinotecan to patients with non-small cell lung cancer.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
omers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate,
or rph thereof, is administered in combination with carboplatin and irinotecan to ts
with non-small cell lung cancer.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered with doxetaxol to patients with non-small cell lung cancer
who have been previously treated with VP 16 and radiotherapy.
In certain embodiments, a compound provided , or an enantiomer or a mixture of
enantiomers thereof, or a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered in combination with carboplatin and/or taxotere, or in
combination with carboplatin, pacilitaxel and/or thoracic radiotherapy to patients with non-small
cell lung cancer.
In certain embodiments, a nd provided herein, or an enantiomer or a e of
enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate,
or polymorph thereof, is stered in combination with taxotere to patients with stage IIIB or
IV non-small cell lung cancer.
In n embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered in combination with oblimersen (Genasense®) to patients
with small cell lung cancer.
In certain embodiments, a nd provided herein, e.g., the compound of Formula I,
or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with
ABT-737 (Abbott Laboratories) and/or obatoclax (GXlS-070) to patients with lymphoma and
other blood cancers.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or rph f, is stered alone or in combination with a second active ingredient
such as vinblastine or fludarabine to patients with various types of lymphoma, ing, but not
limited to, n’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma,
cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade
follicular lymphoma.
In certain embodiments, a compound provided herein, or an omer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, ate,
or polymorph thereof, is administered in ation with taxotere, IL-2, IFN, GM-CSF,
PLX4032 (Plexxikon) and/or dacarbazine to patients with various types or stages of melanoma.
In certain embodiments, a nd provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered alone or in combination with vinorelbine to patients with
malignant mesothelioma, or stage IIIB non-small cell lung cancer with pleural implants or
malignant pleural effusion mesothelioma syndrome.
In certain ments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered to patients with s types or stages of multiple
myeloma in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin,
vinblastine, lan, han, cyclophosphamide, IFN, palmidronate, prednisone,
bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON—A, vincristine, or a combination
thereof.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers f, or a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered to patients with ed or refractory multiple a in
combination with doxorubicin (Doxil®), vincristine and/or dexamethasone (Decadron®).
In certain embodiments, a compound provided herein, or an omer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered to patients with various types or stages of ovarian cancer
such as peritoneal carcinoma, papillary serous carcinoma, tory ovarian cancer or recurrent
ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin,
, paclitaxel, thasone, or a combination thereof.
In n embodiments, a nd ed herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered to patients with various types or stages of prostate cancer,
in combination with xeloda, 5 FU/LV, gemcitabine, irinotecan plus gemcitabine,
cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir,
paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, denderon or a combination thereof.
In certain embodiments, a compound provided herein, or an enantiomer or a e of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered to patients with various types or stages of renal cell cancer,
in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination
thereof.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph f, is administered to patients with various types or stages of logic,
uterus or soft tissue sarcoma cancer in combination with IFN, a COX-2 inhibitor such as
ex®, and/or sulindac.
In certain embodiments, a compound ed herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered to patients with various types or stages of solid tumors in
combination with celebrex, ide, cyclophosphamide, docetaxel, apecitabine, IFN,
tamoxifen, IL-2, GM-CSF, or a combination thereof
In certain embodiments, a compound provided , or an enantiomer or a mixture of
omers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered to patients with scleroderma or cutaneous vasculitis in
combination with celebrex, ide, cyclophosphamide, docetaxel, apecitabine, IFN,
tamoxifen, IL-2, GM-CSF, or a combination thereof
Also encompassed herein is a method of increasing the dosage of an anti-cancer drug or
agent that can be safely and effectively administered to a t, which comprises administering
to the patient (6.g. a human) or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or rph thereof.
Patients that can benefit by this method are those likely to suffer from an adverse effect
associated with anti-cancer drugs for treating a specific cancer of the skin, subcutaneous tissue,
lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal, , prostate,
breast, colorectal, or ations thereof The administration of a compound provided herein,
or an enantiomer or a mixture of omers thereof, or a ceutically acceptable salt,
solvate, hydrate, co-crystal, ate, or polymorph thereof, alleviates or reduces adverse effects
which are of such severity that it would ise limit the amount of anti-cancer drug.
In one ment, a compound provided herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered orally and daily in an amount ranging from about 0.1 to
about 150 mg, from about 1 to about 50 mg, or from about 2 to about 25 mg, prior to, , or
after the occurrence of the adverse effect associated with the administration of an anti-cancer
drug to a patient. In certain embodiments, a compound provided herein, or an enantiomer or a
mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph f, is administered in combination with specific agents such as
heparin, aspirin, coumadin, or G-CSF to avoid adverse s that are associated with anti-
cancer drugs such as but not limited to neutropenia or thrombocytopenia.
In one embodiment, a nd ed herein, or an enantiomer or a e of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, is administered to patients with diseases and disorders ated with or
characterized by, undesired angiogenesis in combination with additional active ingredients,
including, but not limited to, anti-cancer drugs, anti-inflammatories, antihistamines, antibiotics,
and steroids.
In another ment, encompassed herein is a method of treating, preventing and/or
managing cancer, which comprises administering the nd, or an enantiomer or a mixture
of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal,
clathrate, or rph thereof, in conjunction with (e.g. before, during, or after) conventional
therapy including, but not limited to, surgery, immunotherapy, biological y, radiation
therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer. The
combined use of the compound provided herein and conventional therapy may provide a unique
treatment regimen that is unexpectedly effective in certain patients. Without being limited by
, it is believed that the compound of Formula I may provide additive or synergistic effects
when given concurrently with conventional therapy.
As sed elsewhere herein, encompassed herein is a method of reducing, treating
and/or preventing adverse or undesired effects associated with conventional y including,
but not d to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological
therapy and immunotherapy. A compound ed herein, or an enantiomer or a mixture of
enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph f, and other active ingredient can be administered to a t prior to,
during, or after the occurrence of the adverse effect associated with conventional therapy.
In one embodiment, the compound can be administered in an amount ranging from about
0.1 to about 150 mg, from about 1 to about 25 mg, from about 2 to about 10 mg, or about 0.5 to
about 4 mg orally and daily alone, or in combination with a second active agent disclosed herein
(see, e.g., section 4.3), prior to, during, or after the use of conventional y.
In certain embodiments, a compound provided herein, or an enantiomer or a mixture of
omers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate,
or polymorph thereof, and doxetaxol are administered to patients with non-small cell lung cancer
who were previously treated with carbo/VP 16 and radiotherapy.
.6 ceutical Compositions
Pharmaceutical compositions can be used in the preparation of individual, single unit
dosage forms. Pharmaceutical compositions and dosage forms provided herein comprise a
compound, or a pharmaceutically acceptable salt, solvate, e, stereoisomer, clathrate, or
prodrug thereof. Pharmaceutical itions and dosage forms provided herein may further
comprise one or more excipients.
Pharmaceutical compositions and dosage forms provided herein may also comprise one
or more additional active ingredients. Examples of optional second, or additional, active
ients are disclosed herein.
Single unit dosage forms are suitable for oral, mucosal (e.g, nasal, sublingual, vaginal,
, or rectal), parenteral (e.g., aneous, intravenous, bolus injection, intramuscular, or
rterial), topical (e.g, eye drops or other ophthalmic preparations), transdermal or
transcutaneous administration to a patient. Examples of dosage forms include, but are not
limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; s;
lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels;
liquid dosage forms suitable for oral or l administration to a patient, including
sions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-
in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral
administration to a patient; eye drops or other ophthalmic preparations suitable for topical
stration; and sterile solids (e.g, crystalline or ous solids) that can be reconstituted
to provide liquid dosage forms suitable for eral administration to a patient.
The composition, shape, and type of dosage forms provided herein will lly vary
depending on their use. For example, a dosage form used in the acute treatment of a disease may
contain larger amounts of one or more of the active ingredients it comprises than a dosage form
used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may
contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage
form used to treat the same disease. These and other ways in which specific dosage forms
provided herein will vary from one another will be readily apparent to those skilled in the art.
See, e.g., Remington ’s Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
l pharmaceutical compositions and dosage forms comprise one or more excipients.
Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting
examples of suitable excipients are provided herein. Whether a particular excipient is suitable
for incorporation into a ceutical composition or dosage form depends on a variety of
s well known in the art including, but not limited to, the way in which the dosage form will
be stered to a patient. For e, oral dosage forms such as tablets may contain
excipients not suited for use in eral dosage forms. The suitability of a particular excipient
may also depend on the specific active ingredients in the dosage form. For example, the
decomposition of some active ingredients may be accelerated by some excipients such as lactose,
or when exposed to water. Active ingredients that comprise primary or secondary amines are
particularly susceptible to such accelerated osition. uently, provided herein are
pharmaceutical compositions and dosage forms that contain , if any, lactose other mono- or
di-saccharides. As used herein, the term se-free” means that the amount of lactose present,
if any, is insufficient to substantially increase the degradation rate of an active ingredient.
Lactose-free compositions provided herein can comprise ents that are well known
in the art and are listed, for example, in the US. Pharmacopeia (USP) 25-NF20 (2002). In
general, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in
ceutically compatible and pharmaceutically acceptable amounts. In one embodiment,
lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized
starch, and magnesium stearate.
Also provided herein are anhydrous pharmaceutical compositions and dosage forms
comprising active ingredients, since water can facilitate the ation of some compounds.
For example, the addition of water (6.g. is widely accepted in the pharmaceutical arts as a
, 5%)
means of simulating long-term storage in order to determine characteristics such as shelf-life or
the ity of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles
& Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat
accelerate the decomposition of some compounds. Thus, the effect of water on a formulation
can be of great significance since moisture and/or humidity are commonly encountered during
manufacture, handling, packaging, storage, shipment, and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms may be prepared using
ous or low moisture containing ingredients and low moisture or low humidity conditions.
ceutical compositions and dosage forms that comprise lactose and at least one active
ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial
contact with moisture and/or humidity during manufacturing, packaging, and/or storage is
expected.
An anhydrous pharmaceutical composition should be prepared and stored such that its
anhydrous nature is ined. Accordingly, anhydrous compositions are preferably packaged
using materials known to t exposure to water such that they can be ed in suitable
formulary kits. Examples of suitable packaging include, but are not limited to, hermetically
sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
Also provided herein are pharmaceutical compositions and dosage forms that comprise
one or more compounds that reduce the rate by which an active ient will decompose. Such
compounds, which are referred to herein as “stabilizers,” include, but are not limited to,
antioxidants such as ascorbic acid, pH buffers, or salt buffers.
.7 Oral Dosage Forms
Pharmaceutical compositions that are suitable for oral administration can be presented as
discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets,
capsules, and liquids (e.g., flavored syrups). Such dosage forms n predetermined s
of active ients, and may be prepared by s of pharmacy well known to those skilled
in the art. See generally, ton ’s Pharmaceutical Sciences, 18th ed., Mack Publishing,
Easton PA (1990).
Typical oral dosage forms are prepared by combining the active ingredients in an
intimate admixture with at least one excipient according to conventional pharmaceutical
nding ques. Excipients can take a wide y of forms depending on the form of
preparation desired for administration. For example, excipients suitable for use in oral liquid or
aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring
agents, preservatives, and coloring . Examples of excipients suitable for use in solid oral
dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to,
starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and
disintegrating agents.
Because of their ease of administration, tablets and es represent the most
advantageous oral dosage unit forms, in which case solid excipients are employed. If desired,
tablets can be coated by rd aqueous or nonaqueous techniques. Such dosage forms can be
prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and
dosage forms are prepared by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then g the product into the desired
presentation if necessary.
For e, a tablet can be prepared by compression or molding. Compressed tablets
can be prepared by compressing in a suitable machine the active ingredients in a free-flowing
form such as powder or granules, optionally mixed with an ent. Molded tablets can be
made by molding in a suitable machine a mixture of the powdered compound moistened with an
inert liquid diluent.
Examples of excipients that can be used in oral dosage forms provided herein include, but
are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato
starch, or other starches, n, natural and tic gums such as acacia, sodium te,
alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g.,
ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium ymethyl
cellulose), polyvinyl pyrrolidone, methyl ose, latinized starch, hydroxypropyl methyl
cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
Suitable forms of microcrystalline cellulose include, but are not limited to, the materials
sold as AVICEL-PH- l 0 l, AVICEL-PH-103 AVICEL RC-S 81, AVICEL-PH- l 05 (available
from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and
mixtures thereof. An specific binder is a mixture of rystalline cellulose and sodium
carboxymethyl cellulose sold as AVICEL RC-58l. Suitable anhydrous or low moisture
excipients or additives e AVICEL-PH-103TM and Starch 1500 LM.
Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms
disclosed herein e, but are not limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, tes, kaolin, mannitol, silicic acid, sorbitol,
, pre-gelatinized starch, and mixtures thereof. The binder or filler in ceutical
compositions of the invention is typically present in from about 50 to about 99 weight percent of
the pharmaceutical composition or dosage form.
Disintegrants are used in compositions to provide tablets that disintegrate when exposed
to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in
storage, while those that contain too little may not disintegrate at a desired rate or under the
desired conditions. Thus, a sufficient amount of disintegrant that is r too much nor too
little to detrimentally alter the release of the active ients should be used to form solid oral
dosage forms. The amount of disintegrant used varies based upon the type of ation, and is
readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to
about 5 weight percent of egrant.
Disintegrants that can be used in pharmaceutical compositions and dosage forms include,
but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose,
croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or
tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other
celluloses, gums, and mixtures thereof.
Lubricants that can be used in pharmaceutical compositions and dosage forms e,
but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil,
glycerin, sorbitol, mannitol, polyethylene , other glycols, stearic acid, sodium lauryl sulfate,
talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive
oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and es
thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL200,
manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica
(marketed by Degussa Co. of Plano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold
by Cabot Co. of Boston, MA), and mixtures thereof If used at all, lubricants are typically used
in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage
forms into which they are incorporated.
In one ment, a solid oral dosage form of the invention ses a compound
ed herein, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,
colloidal anhydrous silica, and gelatin.
.8 Delayed Release Dosage Forms
Active ingredients may be administered by controlled release means or by ry
devices that are well known to those of ordinary skill in the art. es include, but are not
limited to, those described in US. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 123; and
4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 476, 5,354,556, and
,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to
provide slow or controlled-release of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic
systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination f
to provide the desired release profile in varying tions. Suitable controlled-release
formulations known to those of ordinary skill in the art, including those described herein, can be
readily selected for use with the active ingredients provided herein. Thus, provided herein are
single unit dosage forms suitable for oral administration such as, but not limited to, s,
capsules, gelcaps, and caplets that are adapted for controlled-release.
All controlled-release pharmaceutical products have a common goal of improving drug
therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is characterized by a minimum of
drug substance being ed to cure or control the condition in a minimum amount of time.
Advantages of controlled-release formulations include ed activity of the drug, reduced
dosage ncy, and sed patient compliance. In addition, controlled-release formulations
can be used to affect the time of onset of action or other characteristics, such as blood levels of
the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
Most controlled-release formulations are ed to initially release an amount of drug
(active ingredient) that promptly produces the desired therapeutic effect, and lly and
continually release of other amounts of drug to maintain this level of therapeutic or prophylactic
effect over an extended period of time. In order to maintain this constant level of drug in the
body, the drug must be released from the dosage form at a rate that will replace the amount of
drug being metabolized and excreted from the body. Controlled-release of an active ingredient
can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes,
water, or other physiological ions or nds.
5.9 Parenteral Dosage Forms
Parenteral dosage forms can be administered to patients by various routes including, but
not limited to, subcutaneous, intravenous (including bolus injection), uscular, and
intraarterial. Because their administration typically bypasses patients’ natural defenses against
inants, eral dosage forms are preferably sterile or e of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms include, but are not limited
to, solutions ready for ion, dry ts ready to be dissolved or suspended in a
pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
Suitable vehicles that can be used to provide parenteral dosage forms are well known to
those skilled in the art. Examples include, but are not d to: Water for Injection USP;
aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection,
Dextrose Injection, Dextrose and Sodium Chloride ion, and ed Ringer’s Injection;
water-miscible vehicles such as, but not d to, ethyl alcohol, polyethylene glycol, and
polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed
oil, peanut oil, sesame oil, ethyl oleate, pyl myristate, and benzyl benzoate.
Compounds that increase the solubility of one or more of the active ingredients disclosed
herein can also be incorporated into the parenteral dosage forms provided herein. For example,
cyclodextrin and its derivatives can be used to se the solubility of a nd and its
derivatives. See, e. g., US. Patent No. 5,134,127, which is incorporated herein by reference.
.10 Topical and Mucosal Dosage Forms
Topical and mucosal dosage forms provided herein include, but are not limited to, sprays,
aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other
forms known to one of skill in the art. See, e.g., Remington ’s Pharmaceutical Sciences, 16th and
18th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical
Dosage Forms, 4th ed., Lea & Febiger, Philadelphia . Dosage forms suitable for treating
mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
Suitable excipients (e.g. carriers and diluents) and other materials that can be used to
provide topical and mucosal dosage forms are well known to those skilled in the pharmaceutical
arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage
form will be applied. With that fact in mind, typical excipients include, but are not d to,
water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,
isopropyl palmitate, mineral oil, and es thereof to form solutions, emulsions or gels, which
are non-toxic and pharmaceutically able. Moisturizers or ants can also be added to
pharmaceutical itions and dosage forms if desired. Examples of such additional
ingredients are well known in the art. See, e.g. ’s Pharmaceutical Sciences, 16th and
, Remington
18th eds., Mack Publishing, Easton PA (1980 & 1990).
The pH of a pharmaceutical composition or dosage form may also be adjusted to improve
delivery of one or more active ingredients. rly, the polarity of a solvent carrier, its ionic
strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also
be added to pharmaceutical compositions or dosage forms to advantageously alter the
hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In
this regard, stearates can serve as a lipid e for the formulation, as an emulsifying agent or
surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, es
or solvates of the active ingredients can be used to further adjust the properties of the resulting
ition.
5.11 Kits
In some embodiments provided herein, active ingredients are preferably not administered
to a patient at the same time or by the same route of administration. Thus, provided herein are
kits which, when used by the medical practitioner, can simplify the administration of appropriate
amounts of active ingredients to a patient.
In one embodiment a kit provided herein comprises a compound ed herein, or a
ceutically acceptable salt, solvate or hydrate f. Kits may further comprise
additional active , including but not limited to those disclosed herein.
Kits provided herein may further comprise devices that are used to administer the active
ients. Examples of such devices include, but are not limited to, syringes, drip bags,
patches, and inhalers.
Kits may further comprise cells or blood for transplantation as well as pharmaceutically
acceptable vehicles that can be used to administer one or more active ingredients. For example,
if an active ingredient is provided in a solid form that must be reconstituted for parenteral
administration, the kit can comprise a sealed container of a suitable vehicle in which the active
ingredient can be dissolved to form a particulate-free sterile solution that is le for
parenteral administration. Examples of pharmaceutically acceptable es include, but are not
limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium
Chloride Injection, Ringer’s Injection, se ion, Dextrose and Sodium Chloride
Injection, and Lactated Ringer’s Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene , and polypropylene glycol; and non-aqueous vehicles such as,
WO 49299
but not d to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
.12 Antibodies
Antibodies that immunospecifically bind to CRBN CRBN antibodies) provided
herein include, but are not limited to, synthetic antibodies, monoclonal antibodies, recombinantly
produced antibodies, multispeciflc antibodies (including bi-specific antibodies), human
antibodies, humanized antibodies, chimeric antibodies, intrabodies, single-chain Fvs (scFv) (e.g.,
including monospecif1c, bispeciflc, eta), camelized antibodies, Fab fragments, F(ab’) fragments,
disulf1de-linked Fvs (dev), anti-idiotypic (anti-Id) antibodies, and antigen- or epitope-binding
fragments of any of the above.
In particular, antibodies provided herein include immunoglobulin molecules and
immunologically active ns of immunoglobulin les, z'.e., molecules that n an
antigen binding site that immunospecifically binds to a CRBN antigen. The immunoglobulin
molecules provided herein can be of any type (e.g, IgG, IgE, IgM, IgD, IgA and IgY), class (e.g,
IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule. In a specific
embodiment, an antibody provided herein is an IgG dy, and, in certain embodiments, an
IgGl or IgG4.
Also provided herein is an isolated CRBN antibody, for example, “CRBN70,” as
prepared according to Example 6.20 or 6.21 below. In one embodiment, the antibody is a
polyclonal antibody. In another embodiment, the antibody is a onal antibody. In some
embodiments, the antibody is a rabbit polyclonal antibody. In other embodiments, the antibody
is a rabbit monoclonal antibody.
In another embodiment, ed herein is an ed antibody which
immunospecifically binds to the epitope having an amino acid sequence EEFHGRTLHDDDC
(SEQ ID: 1). In another embodiment, the antibody immunospecifically binds to the epitope
having an amino acid sequence EEFHGRTLHDDDC (SEQ ID: 1), wherein the peptide is
coupled to e Limpet Hemocyanin (KLH). In one ment, the antibody is a
polyclonal antibody. In another embodiment, the antibody is a monoclonal antibody. In some
embodiments, the antibody is a rabbit polyclonal antibody. In other embodiments, the dy
is a rabbit monoclonal antibody. In n embodiments, the antibody immunospecif1cally binds
peptide 65-76 (SEQ ID NO:1) of human CRBN (SEQ ID NO:12).
In certain embodiments, provided herein is an antibody that immunospecif1cally binds
CRBN and comprises a heavy chain having the amino acid sequence depicted in SEQ ID NO:5,
or the VH domain, VH CDRl, VH CDR2, and/or VH CDR3 thereof. In other embodiment, the
antibody immunospecif1cally binds CRBN and comprises a light chain having the amino acid
sequence depicted in SEQ ID NO:7, or the VL domain, VL CDRl, VL CDR2, and/or VL CDR3
f. In some embodiments, the antibody comprises a heavy chain having the amino acid
sequence depicted in SEQ ID NO:5, or the VH domain, VH CDRl, VH CDR2, and/or VH
CDR3 thereof; and a light chain having the amino acid ce depicted in SEQ ID NO:7, or
the VL domain, VL CDRl, VL CDR2, and/or VL CDR3 thereof. In certain embodiments, the
antibody immunospecif1cally binds CRBN and comprises a heavy chain having the amino acid
sequence depicted in SEQ ID N09, or the VH domain, VH CDRl, VH CDR2, and/or VH
CDR3 thereof. In other embodiment, the antibody specif1cally binds CRBN and
comprises a light chain having the amino acid sequence depicted in SEQ ID NO: 1 l, or the VL
domain, VL CDRl, VL CDR2, and/or VL CDR3 thereof In some embodiments, the antibody
comprises a heavy chain having the amino acid ce depicted in SEQ ID NO:9, or the VH
domain, VH CDRl, VH CDR2, and/or VH CDR3 thereof; and a light chain having the amino
acid sequence depicted in SEQ ID NO: 1 l, or the VL domain, VL CDRl, VL CDR2, and/or VL
CDR3 thereof. In certain embodiments, the antibody immunospeciflcally binds peptide 65-76
(SEQ ID NO: 1) of human CRBN (SEQ ID NO: 12).
Any of the CRBN dies provided herein can be used in any of the methods provided
herein
Variants and derivatives of dies include antibody fragments that retain the ability to
specifically bind to an epitope. Exemplary fragments include Fab fragments (an antibody
fragment that ns the antigen-binding domain and comprises a light chain and part of a
heavy chain bridged by a disulfide bond); Fab’ (an antibody fragment containing a single anti-
binding domain comprising an Fab and an additional portion of the heavy chain h the
hinge region); F(ab’)2 (two Fab’ molecules joined by interchain disulfide bonds in the hinge
regions of the heavy chains; the Fab’ molecules may be directed toward the same or different
epitopes); a bispecific Fab (a Fab molecule having two antigen binding domains, each of which
may be directed to a different epitope); a single chain Fab chain sing a variable region,
also known as, a st (the variable, antigen-binding determinative region of a single light and
heavy chain of an antibody linked together by a chain of 10-25 amino ; a disulfide-linked
2012/035429
FV, or dst (the variable, antigen-binding determinative region of a single light and heavy chain
of an antibody linked together by a disulfide bond); a camelized VH (the variable, antigen-
binding determinative region of a single heavy chain of an antibody in which some amino acids
at the VH interface are those found in the heavy chain of naturally occurring camel dies); a
bispecific sFV (a sFV or a dst molecule having two n-binding domains, each of which
may be directed to a different epitope); a diabody (a dimerized sFV formed when the VH domain
of a first sFV assembles with the VL domain of a second sFV and the VL domain of the first sFV
assembles with the VH domain of the second st; the two antigen-binding regions of the
y may be directed towards the same or different es); and a triabody (a trimerized
sFV, formed in a manner similar to a diabody, but in which three antigen-binding domains are
created in a single complex; the three antigen binding domains may be directed towards the same
or different epitopes). Derivatives of antibodies also include one or more CDR sequences of an
antibody combining site. The CDR sequences may be linked together on a scaffold when two or
more CDR sequences are present. In certain embodiments, the anti-CRBN antibody comprises a
single-chain FV (“scFv”). scFvs are antibody fragments comprising the VH and VL domains of
an antibody, wherein these s are present in a single polypeptide chain. Generally, the
scFv polypeptide fiarther comprises a polypeptide linker between the VH and VL domains which
enables the scFV to form the desired structure for antigen binding. For a reView of scFvs see
Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds.
er-Verlag, New York, pp. 5 (1994).
Provided herein are antibodies that immunospecifically bind to a CRBN epitope, the
antibodies comprising derivatives of the VH and VL chains described herein that
immunospecifically bind to a CRBN antigen or a CRBN epitope.. Standard techniques known to
those of skill in the art can be used to uce mutations in the nucleotide sequence encoding a
molecule of the invention, including, for example, irected nesis and PCR-mediated
nesis which results in amino acid substitutions. Preferably, the derivatives include less
than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid
substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than
4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid
tutions relative to the original molecule. In a preferred embodiment, the derivatives have
vative amino acid substitutions are made at one or more predicted non-essential amino
2012/035429
acid residues. A “conservative amino acid substitution” is one in which the amino acid residue is
replaced with an amino acid residue having a side chain with a r charge. Families of
amino acid residues having side chains with similar charges have been defined in the art. These
families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side
chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., e, asparagine,
glutamine, serine, ine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine,
leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains
(e.g., threonine, valine, isoleucine) and ic side chains (e.g., tyrosine, phenylalanine,
tryptophan, histidine). Alternatively, mutations can be introduced randomly along all or part of
the coding sequence, such as by saturation mutagenesis, and the resultant mutants can be
screened for biological activity to identify mutants that retain ty. Following mutagenesis,
the encoded protein can be sed and the activity of the protein can be determined.
In another embodiment, an dy that immunospecif1cally binds to a CRBN epitope
comprises an amino acid ce that is at least 35%, at least 40%, at least 45%, at least 50%,
at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at
least 90%, at least 95%, or at least 99% identical to the amino acid sequence of CGNl-ll OR
CGNl-l l, or an n-binding fragment thereof, such as a VH domain, VL domain, VH
chain, or VL chain. In one embodiment, an dy that immunospecif1cally binds to a CRBN
epitope comprises an amino acid sequence that is at least 35%, at least 40%, at least 45%, at least
50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least
85%, at least 90%, at least 95%, or at least 99% identical to an amino acid sequence depicted in
SEQ ID NOS:5, 7, 9 or 11.
In a specific embodiment, an antibody that specifically binds a CRBN antigen
comprises an amino acid sequence of a VH chain and/or an amino acid sequence a VL chain
encoded by a nucleotide sequence that hybridizes to (l) the complement of a nucleotide sequence
encoding any one of the VH and/or VL chains depicted in SEQ ID NOS:5 or 9 (H chain) and/or
SEQ ID NOS:7 or 11 (L chain) under stringent conditions (e.g., hybridization to filter-bound
DNA in 6x sodium chloride/sodium e (SSC) at about 45° C followed by one or more
washes in 0.2XSSC/0.l% SDS at about 50-65° C) under highly stringent conditions (e.g,
hybridization to filter-bound nucleic acid in 6XSSC at about 45° C followed by one or more
washes in 0. lXSSC/0.2% SDS at about 68° C), or under other stringent hybridization conditions
which are known to those of skill in the art (see, for example, Ausubel, F.M. et al., eds., 1989,
Current Protocols in Molecular y, Vol. I, Green Publishing Associates, Inc. and John
Wiley & Sons, Inc., New York at pages 6.3.1-6.3.6 and 2.10.3).
The anti-CRBN antibodies may be from any animal origin including birds and mammals
(e.g., human, , , sheep, rabbit, goat, guinea pig, camel, horse, or chicken). In
certain embodiments, the anti-CRBN antibodies are human or humanized monoclonal antibodies.
As used herein, “human” antibodies include antibodies having the amino acid sequence of a
human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or
from mice that express antibodies from human genes.
In certain embodiments, the anti-CRBN antibodies are fillly human antibodies, such as fillly
human dies that immunospecifically bind a CRBN polypeptide, a CRBN polypeptide
fragment, or a CRBN epitope. Such fully human dies would be advantageous over fiJlly
mouse (or other full or partial non-human species antibodies), humanized antibodies, or chimeric
antibodies to minimize the development of unwanted or unneeded side effects, such as immune
responses directed toward non-fully human antibodies (e.g., anti-CRBN antibodies derived from
other species) when stered to the subject.
Anti-CRBN antibodies provided herein may be monospecific, bispecif1c, trispecif1c or of greater
multispecificity. Multispecific antibodies may be specific for different epitopes of a CRBN
polypeptide or may be specific for both a CRBN polypeptide as well as for a logous
epitope, such as a heterologous polypeptide or solid t material. In certain embodiments,
the antibodies ed herein are monospecific for a given epitope of a CRBN polypeptide and
do not specifically bind to other es.
In certain embodiments, provided herein are anti-CRBN antibodies that immunospecifically bind
to a CRBN epitope (e.g., EEFHGRTLHDDD (SEQ ID NO: 1) or peptide 65-76 of human CRBN
(SEQ ID NO: 12)) or a CRBN antigen, as well as methods of use thereof.
Standard techniques known to those of skill in the art can be used to introduce mutations
in the nucleotide sequence encoding an anti-CRBN provided , ing, for example, site-
directed mutagenesis and PCR-mediated mutagenesis which results in amino acid substitutions.
A “conservative amino acid tution” is one in which the amino acid residue is replaced with
an amino acid residue having a side chain with a similar charge. Families of amino acid residues
having side chains with similar charges have been defined in the art. These families include
amino acids with basic side chains (e.g, lysine, arginine, histidine), acidic side chains (e.g,
aspartic acid, glutamic acid), ged polar side chains (e.g, glycine, asparagine, glutamine,
serine, ine, ne, cysteine), nonpolar side chains (e.g, alanine, valine, e,
isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g,
threonine, valine, isoleucine) and aromatic side chains (e.g, tyrosine, phenylalanine, tryptophan,
histidine). atively, mutations can be introduced randomly along all or part of the coding
sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for
biological activity to identify mutants that retain activity. Following mutagenesis, the encoded
n can be expressed and the activity of the protein can be determined.
In some embodiments, the antibody is a fully human anti-human CRBN antibody, such as
a fially human monoclonal antibody. Fully human antibodies may be produced by any method
known in the art. Exemplary methods include immunization with a CRBN antigen (any CRBN
polypeptide capable of eliciting an immune se, and optionally conjugated to a carrier) of
transgenic animals (e.g, mice) that are capable of producing a repertoire of human antibodies in
the absence of endogenous immunoglobulin production; see, e. g., Jakobovits et al., (1993) Proc.
Natl. Acad. Sell, 90:25.51; Jakobovits et al., (1993) Nature, 362255 258 (1993); Braggermann et
al., (1993) Year in Immanol., 7:33. Other methods of producing anti-CRBN dies can be
found in the Examples provided herein.
Alternatively, fully human antibodies may be generated through the in vitro screening of phage
display antibody libraries; see e.g., Hoogenboom et al., J. Mol. Biol., 227:381 (1991); Marks et
al., J. Mol. Biol., 222:581 (1991), orated herein by nce. Various antibody-containing
phage display libraries have been described and may be readily prepared by one skilled in the art.
Libraries may contain a diversity of human antibody sequences, such as human Fab, Fv, and
scFv fragments, that may be screened t an appropriate .
The anti-CRBN antibodies include antibodies that are chemically modified, l'.e., by the
covalent attachment of any type of molecule to the antibody. For e, but not by way of
limitation, the dy derivatives include antibodies that have been ally modified, e.g.,
by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known
protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc.
Any ofnumerous chemical modifications may be carried out by known techniques, including,
but not limited to specific chemical cleavage, acetylation, formulation, metabolic synthesis of
tunicamycin, etc. Additionally, the antibody may contain one or more non-classical amino acids.
In certain embodiments, anti-CRBN antibodies that immunospecif1cally bind to a CRBN
antigen comprise a framework region known to those of skill in the art (e.g., a human or non-
human fragment). The framework region may, for example, be lly occurring or consensus
framework regions. In some embodiments, the framework region of an anti-CRBN antibody is
human (see, e.g., Chothia et al., 1998, J. M01. Biol. 278:457-479 for a listing of human
framework regions, which is incorporated by reference herein in its entirety). See also Kabat et
al. (1991) Seguences of Proteins of Immunological Interest (US. Department of Health and
Human es, Washington, DC.) 5th ed.
In certain embodiments, the anti-CRBN antibodies provided herein are chimeric or
humanized antibodies. In some embodiments, the dies provided herein se human
framework regions with one or more amino acid substitutions at one, two, three or more of the
following residues: (a) rare ork residues that differ between the murine antibody
framework (z'.e., donor antibody framework) and the human antibody framework (z'.e., acceptor
antibody framework); (b) Venier zone residues when ing n donor antibody
framework and acceptor antibody framework; (c) interchain packing residues at the VH/VL
interface that differ between the donor antibody ork and the acceptor antibody framework;
(d) canonical residues which differ n the donor antibody framework and the acceptor
antibody framework sequences, ularly the framework s crucial for the definition of
the canonical class of the murine antibody CDR loops; (e) residues that are adjacent to a CDR; (g)
residues capable of interacting with the antigen; (h) residues capable of interacting with the CDR;
and (i) contact es between the VH domain and the VL domain. In certain embodiments,
antibodies that immunospecifically bind to a CRBN antigen comprising the human framework
s with one or more amino acid substitutions at one, two, three or more of the above-
identif1ed residues are antagonistic CRBN antibodies.
In other embodiments, fiasion proteins comprising an anti-CRBN antibody are provided
herein that immunospecifically binds to a CRBN antigen and a heterologous polypeptide.
.13 Diagnostic Use of Antibodies
Labeled CRBN antibodies provided herein and derivatives and analogs thereof, which
immunospecif1cally bind to a CRBN antigen can be used for diagnostic purposes to detect,
diagnose, or monitor CRBN expression levels or a CRBN-mediated disease in a patient.
In some embodiments, provided herein are methods of utilizing a CRBN antibody to
measure sion levels of CRBN in patient tumor or host cells, to predict clinical response to
therapy with omide, lenalidomide, pomalidomide, or 3-(5-aminomethyloxo-4H—
quinazolinyl)-piperidine-2,6-dione, a isomer thereof, or a pharmaceutically able
salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Also provided herein are
methods of utilizing a CRBN antibody provided herein to measure expression levels of CRBN in
patient tumor or host cells, to monitor clinical response to therapy with thalidomide,
lenalidomide, pomalidomide, or 3-(5-aminomethyloxo-4H—quinazolinyl)-piperidine-2,6-
dione, a isomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof Also provided herein are methods of utilizing a CRBN antibody
ed herein to measure sion levels of CRBN in patient tumor or host cells, to monitor
patient ance to dosing to therapy with thalidomide, domide, pomalidomide, or 3-(5-
aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione, a stereoisomer thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
Also provided herein are methods of utilizing a CRBN antibody provided herein to e
expression levels of CRBN in patient tumor or host cells, to monitor development of resistance
to therapy with thalidomide, lenalidomide, pomalidomide, or 3-(5-aminomethyloxo-4H—
quinazolinyl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically able
salt, e, hydrate, stal, clathrate, or polymorph f.
Provided herein are diagnostic assays for diagnosing a CRBN-mediated disease
comprising: (a) assaying for the level of a CRBN antigen in cells or a tissue sample of an
individual using one or more antibodies of the invention that specif1cally bind to a
CRBN antigen; and (b) comparing the level of the CRBN antigen with a control level, e.g., levels
in normal tissue samples, whereby an increase in the assayed CRBN antigen level compared to
the control level of the CRBN antigen is indicative of a CRBN-mediated disease.
Antibodies provided herein can be used to assay CRBN antigen levels in a biological
sample using classical immunohistological methods as described herein or as known to those of
skill in the art (e.g., see Jalkanen et al., 1985, J. Cell. Biol. 101:976-985; and Jalkanen et al.,
1987, J. Cell . Biol. 105:3087-3096). Other antibody-based methods useful for detecting protein
gene expression include immunoassays, such as the enzyme linked immunosorbent assay
(ELISA) and the mmunoassay (RIA). le antibody assay labels are known in the art
and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine (1251, 1211),
carbon (14C), sulfur (35S), m (3H), indium (mIn), and technetium (99Tc); luminescent labels,
such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.
ed herein are methods for the detection or CRBN in a patient. In one embodiment,
the method comprises: a) administering (for example, parenterally, subcutaneously, or
intraperitoneally) to a subject an effective amount of a labeled antibody that immunospecif1cally
binds to a CRBN antigen; b) waiting for a time interval following the administering for
permitting the d antibody to preferentially concentrate at sites in the subject where the
CRBN antigen is expressed (and for unbound labeled molecule to be cleared to background
; c) determining background level; and d) detecting the labeled antibody in the subject,
such that detection of labeled antibody above the background level indicates that the subject has
increased CRBN expression. Background level can be ined by various methods including,
comparing the amount of labeled molecule detected to a standard value previously determined
for a particular .
It will be understood in the art that the size of the subject and the imaging system used
will ine the quantity of imaging moiety needed to produce diagnostic images. In the case
of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally
range from about 5 to 20 uries of 99Tc. The labeled antibody will then preferentially
accumulate at the location of cells which contain the specific protein. In vivo tumor imaging is
described in S.W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and
Their nts.” (Chapter 13 in Tumor g: The Radiochemical Detection of Cancer,
S.W. Burchiel and BA. Rhodes, eds., Masson Publishing Inc. .
ing on l variables, including the type of label used and the mode of
administration, the time interval following the administration for permitting the labeled antibody
to preferentially concentrate at sites in the subject and for unbound labeled antibody to be cleared
to background level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. In another embodiment
the time interval following administration is 5 to 20 days or 5 to 10 days.
Presence of the labeled molecule can be detected in the subject using methods known in
the art for in viva scanning. These s depend upon the type of label used. Skilled artisans
will be able to determine the appropriate method for detecting a particular label. Methods and
devices that may be used in the diagnostic methods of the ion include, but are not limited
to, ed tomography (CT), whole body scan such as position emission tomography (PET),
magnetic resonance g (MRI), and sonography.
In a specific embodiment, the molecule is labeled with a sotope and is detected in
the patient using a radiation responsive al instrument (Thurston et al. US. Patent No.
,441,050). In another embodiment, the molecule is labeled with a fluorescent compound and is
detected in the patient using a fluorescence responsive scanning ment. In another
embodiment, the molecule is labeled with a positron emitting metal and is detected in the patient
using positron emission-tomography. In yet another embodiment, the molecule is labeled with a
paramagnetic label and is ed in a patient using magnetic resonance g (MRI).
6. EXAMPLES
Certain embodiments of the invention are illustrated by the following non-limiting
examples.
6.1 Preparation of 3-(4-amin0-l-oxo-1,3-dihydr0-is0indolyl)-
piperidine—2,6-di0ne idomide)
Methyl 2-brom0methyl—3-nz'tr0benzoate
A stirred mixture of methyl 2-methylnitrobenzoate (14.0 g, 71.7 mmol) and N-
bromosuccinimide (15.3 g, 86.1 mmol) in carbon tetrachloride (200 mL) was heated under gentle
reflux for 15 hours while a 100W bulb situated 2 cm away was shining on the flask. The mixture
was filtered and the solid was washed with methylene chloride (50 mL). The filtrate was washed
with water (2x100 mL), brine (100 mL) and dried. The solvent was removed in vacuo and the
residue was purified by flash chromatography (hexane/ethyl e, 8/2) to afford 19 g (96%) of
the product as a yellow solid: mp 70.0-71.5°C; 1H NMR (CDC13) 8 8.12-8.09(dd, J=1.3 and 7.8
Hz, 1H), .94(dd, J=1.3 and 8.2 Hz, 1H), 7.54(t, J=8.0 Hz, 1H). 5.15(s, 2H), 4.00(s, 3H);
13C NMR (CDC13) 5 , 150.58, 134.68, 132.38, 129.08, 127.80, 53.06, 22.69; HPLC,
Water Nove-Pak/C18, 3.9x150 mm, 4 micron, 1mL/min, 240 nm, 40/60 CH3CN/0.1%H3PO4(aq)
7.27 min(98.92%); Anal. Calcd for C9H8N04Br : C, 39.44; H, 2.94; N, 5.1 1 ; Br, 29.15. Found :
C, 39.46; H, 3.00; N, 5.00; Br, 29.1 1.
t—Butyl N- nitr0isoindolinyl)-L-glutamine
Triethylamine (2.9 g, 28.6 mmol) was added dropwise to a stirred mixture of methyl 2-
bromomethylnitrobenzoate (3.5 g, 13.0 mmol) and amine t-butyl ester hydrochloride
(3.1 g, 13.0 mmol) in ydrofuran (90 mL). The mixture was heated to reflux for 24 hours.
To the cooled mixture was added methylene chloride (150 mL) and the mixture was washed with
water (2 x 40 mL), brine (40 mL) and dried. The solvent was removed in vacuo and the residue
was purified by flash chromatography (3% CHgOH in methylene chloride) to afford 2.84 g (60%)
of crude product which was used directly in the next reaction: 1H NMR (CDC13) 8 8.40(d, J=8.1
Hz, 1H), 8.15(d, J=7.5 Hz, 1H), 7.71(t, J=7.8 Hz, 1H), 5.83(s, 1H), 5.61(s, 1H), 5.12(d, J=19.4
Hz, 1H), 5.04-4.98(m, 1H), 4.92(d, J=19.4 Hz, 1H), 2.49-2.22(m, 4H). 1.46(s, 9H); HPLC,
Waters Nova-Pak C18, 3.9x150 mm, 4 micron, 1 mL/min, 240 nm, 25/75
CH3CN/0.1%H3PO4(aq) 6.75 min(99.94%).
N-(I-0x0nz'tr0isoindolinyU-L-glutamine
en chloride gas was bubbled into a stirred 5°C solution of t-butyl N—(1-oxonitro-
olinyl)-L-glutamine (3.6 g, 9.9 mmol) in methylene chloride (60 mL) for 1 hour. The
mixture was then stirred at room temperature for another hour. Ether (40 mL) was added and the
resulting mixture was stirred for 30 minutes. The slurry was filtered, washed with ether and
dried to afford 3.3 g ofthe product: 1H NMR (DMSO-d6) 8 8.45(d, J=8.1 Hz, 1H), 8.15(d, J=7.5
Hz, 1H), 7.83(t, J=7.9 Hz. 1H), 7.24(s, 1H), 6.76(s, 1H), 4.93(s, 2H), .78(dd, J=4.8amd
10.4 Hz, 1H), 2.34-2.10(m, 4H); 13c NMR (DMSO-d6) 5 173.03, 171.88, 165.96, 143.35, 137.49,
134.77, 130.10, 129.61, 126.95, 53.65, 48.13, 31.50, 24.69; Anal. Calcd for N306 : C,
50.82; H, 4.26; N, 13.68. Found : C, 50.53; H. 4.37; N, 13.22.
(I-0x0nitro1'50indolinyl)pz'peridine-2, 6—dz'0ne
A stirred suspension mixture ofN—(l-oxonitroisoindolinyl)-L-glutamine (3.2 g, 10.5 mmol)
in anhydrous methylene chloride (150 mL) was cooled to -40°C with isopropanol/dry ice bath.
Thionyl chloride (0.82 mL, 11.3 mmol) was added dropwise to the cooled mixture followed by
pyridine (0.9 g. 1 1.3 mmol). After 30 min, triethylamine (1.2 g, 11.5 mmol) was added and the
mixture was stirred at -30 to -40°C for 3 hours. The mixture was poured into ice water (200 mL)
and the s layer was extracted with methylene chloride (40 mL). The methylene chloride
solution was washed with water (2 x 60 mL), brine (60 mL) and dried. The solvent was removed
in vacuo and the solid e was slurried with ethyl acetate (20 mL) to give 2.2 g (75%) of the
product as a white solid: mp 285°C; 1H NMR (DMSO-d6) 8 : 1.04(s, 1H), 8.49-8.45(dd, J=0.8
and 8.2 Hz, 1H), 8.21-8.17(dd, J=7.3 Hz, 1H), 7.84(t, J=7.6 Hz, 1H), 5.23-5.15(dd, J=4.9 and
13.0 Hz, 1H), 4.96(dd, J=19.3 and 32.4 Hz, 2H), 3.00-2.85(m, 1H), 2.64-2.49(m, 2H), 2.08-
1.98(m, 1H);13C NMR (DMSO- d6) 8 172.79, 170.69, 165.93, , 137.40, 134.68, 130.15,
129.60, , 51.82, 48.43, 31.16. 22.23; HPLC, Waters Nove-Pak/C18, 3.9x150 mm, 4
, 1 mL/min, 240 nm, 20/80 CH3CN/0.1%H3PO4(aq) 3.67 min(100%); Anal. Calcd for
C13HnN305 : C, 53.98; H, 3.83; N, 14.53. Found : C, 53.92; H, 3.70; N, 14.10.
3- (4-amz'n0-I-0x0-I 3-dihydr0-is0ind0[—2-yl)-pz'perz'dine-2, 6—dz'0ne
A mixture of (S)(1-oxonitroisoindolinyl)piperidine-2,6-dione (1.0 g, 3.5 mmol) and 10%
Pd/C (0.3 g) in methanol (600 mL) was hydrogenated in a Parr-Shaker apparatus at 50 psi of
hydrogen for 5 hours. The mixture was filtered h Celite and the filtrate was trated
in vacuo. The solid was slurried in hot ethyl acetate for 30 min, filtered and dried to afford 0.46
g (51%) ofthe product as a white solid: mp 235.5-239°C; 1H NMR (DMSO-d6) 8 11.01 (s, 1H).
7.19(t, J=7.6 Hz, 1H). 6.90(d. J=7.3 Hz, 1H), 6.78(d, J=7.8 Hz, 1H), 5.42(s, 2H). 5.12(dd. J=5.1
and 13.1 Hz, 1H), 4.17(dd, J=17.0 and 28.8 Hz, 2H), 2.92-2.85(m, 1H). 2.64-2.49(m, 1H). 2.34-
2.27(m, 1H), .99(m, 1H); 13C NMR (DMSO-d6) 8 172.85, 171.19, 168.84, 143.58, 132.22.
128.79, , 1 16.37, 1 10.39, 51.48, 45.49, 31.20, 22.74; HPLC. Waters Nova-Pak/Cl8,
3.9x150 mm, 4 micron, 1 mL/min, 240 nm, 10/90 CH3CN/0.1%H3PO4(aq) 0.96 min(100%);
Chiral analysis, Daicel Chiral Pak AD, 40/60 Hexane/IPA, 6.60 min(99.42%); Anal. Calcd for
C13H13N303 : C, 60.23; H, 5.05; N, 16.21. Found : C, 59.96; H. 4.98; N, 15.84.
3-(4-Aminooxo-1,3-dihydro-isoindolyl)-piperidine-2,6-dione may also be prepared
by s known in the art, for example, as ed in Drugs oft/w Future, 2003, 28(5): 425-
431, the entirety of which is incorporated by reference.
6.2 Preparation of 4-amin0(2,6-di0x0piperidinyl)—1H-is0indole-1,3-
dione (pomalidomide)
The preparation of 4-amino(2,6-dioxopiperidinyl)-1H-isoindole-l,3-dione is
described, for example, in US. patent nos. 169 and 7,709,502, the entirety of each of
which is incorporated by reference.
Into a stirring solution of carboxybenzyloxy-L-glutamine (2.8 g, 10 mmols) in 40 mL
anhydrous THF, 1,1-carbonyldiimidazole (1.92 g, 12 mmols) were added. The on mixture
was heated under reflux for 18 hours. The THF was evaporated and the product was dissolved in
chloroform. The chloroform layer was washed with water and brine and dried over anhydrous
CaSO4, d and evaporated to give white solid. The solid product was crystallized from ethyl
ether to give 2.4 grams crystalline powder (90%). natively, carboxybenzyloxy-L-glutamine
can be cyclized by treating with SOC12 in N,N—dimethylformamide at -70°C to 0°C for 1 hour to
form the product). The reaction mixture was diluted with CHC13 and washed with 5% N32C03,
dried over anhydrous Na2S04, filtered, and evaporated to give 2.5 g (90% yield) S(-)-(3-
benzyloxycarbonylamino)-glutarimide). 1H NMR ) 5 8.2 (1H, s broad), 7.4 (5H, s,
aromatic), 5.8 (1H, d), 5.15 (2H, s), 4.4 (1H, dd, J=4.5, 3), 295-24 (3H, m), 1.86 (1H, d, t,
J=11.5, 6.5). mp. 122-124°C (lit. 122-124°C).
Into a solution of S(-)—(2-benzyloxycarbonylamino)glutarimide (1.2 g, 4.6 mmols) in 15
mL acetic acid glacial, 8 mL of 30% HBr/ acetic acid solution was added at 20°C. The
temperature of reaction mixture was raised to RT and stirred for 1 hour. White solid powder of
S-(-)amino-glutarimide HBr started ing in on e. The solid was filtered and
washed with 5 mL acetic acid glacial and then with ether to give 1.8 g (80%) product. Analysis
on polarimeter of product showed (-) rotation, [a]25D (c=1, water) = -37.5° and confirmed the
product as S-(-)amino-glutarimide. 1H NMR in DMSO-D6 confirmed the product as 2-amino-
L-glutarimide HBr.
Into a solution of (4.18 g, 20 mmols S-(-)amino-glutarimide HBr in 50 mL of
anhydrous DMF, 3.8 g (20 mmols) of 3-nitrophthalic anhydride was added. After adding 100
mL acetic acid (glacial), the reaction mixture was heated at about 70°C to about 80°C for about
24 hours. Thereafter, the solvents were evaporated under vacuum to yield an off-white solid.
On adding 10 mL ethyl alcohol to the solid, an off-white powder product was formed. The
product was separated and washed with 20 mL ethyl alcohol. 1H NMR (DMSO-D6) 5 11.25 (1H,
s broad), 8.35 (1H, d, , 8.25 (1H, d, J=7.0), 8.15 (1H, t, J=8.0), 5.2 (1H, dd, J=5.5, 7.2),
3.00-2.85 (1H, m), 2.65-2.4 (2H, m), 2.15-2.05 (1H, m). mp: 228-229°C (lit. 228.5-229.5°C).
4-Nitro-thalidomide (1 g, 3.3 mmols) was dissolved in 50 mL dioxane/methanol 4:1
mixture and enated in a Parr enater at 40 psi of en in the presence of a Pd/C
% catalyst for about 4 hours. After filtering the reaction mixture through a Celite filtering agent,
the solvents were evaporated under vacuum to yield a yellow powder. The product was
recrystallized from ethyl acetate/dioxane to yield 800 mg (85% purity) of -amino-
thalidomide. 1H NMR in DMSO-D6: 11.10 (1H, s broad), 7.45 (1H, t, J=7. 5), 7.05 (1H, d, J=5.2),
2012/035429
6.95 (1H, d, J=5.2), 6.5 (2H, s , 5.05 (1H, dd, J=5.0, 13.42),2.95-2.80 (1H, m), 2.65-2.5
(2H, m), 2.05-1.95 (1H, m). m.p. 318.2-319.5°C. Absolute configuration was ined by
comparison of specific rotation [a]25D of (R)- and (S)amino(2,6-dioxopiperidinyl)-1H-
isoindole-1,3-dione to the analogous nds R(+)- and S(-)-thalidomide. Analysis on
polarimeter of product showed (-) rotation, [a]25D (C=0.5, dioxane) = -27.700 and confirmed the
product as S(-)amino(2,6-dioxopiperidinyl)-1H-isoindole-1,3-dione.
The two enantiomers were resolved by chiral HPLC column Welk-Ol (10 mm x 750 mm)
and eluted with CH3CN/MeOH/H20 1:1:5 mixture. The retention time for the S(-) enantiomer
was 33.74 minutes and for the R(+) enantiomer 35.62 s at a flow rate of 2 mL/min at 240
nm, respectively.
6.3 Preparation of 3-(5-amin0methyl0x0-4H-quinazolinyl)—
piperidine—2,6-di0ne (Compound B)
To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added
3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 oC. The suspension was stirred at 0 0C for
3 hrs, and then heated to 30 0C for 3 hrs. To the solution, was added HCl (100 mL, 6N). The
resulting suspension was cooled to 0 0C for 1 hr. The suspension was d and washed with
cold water (2 x 10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H
NMR (DMSO-d6) 5 7.69 (brs, 1H, NHH), 7.74 (t, J: 8 Hz, 1H, Ar), 7.92 (dd, J: 1, 8 Hz, 1H,
Ar), 8.13 (dd, .1: 1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); 13C NMR (DMSO-
d6)5125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
To a mixture of 3-nitro-phthalamic acid (24.6 g, 117 mmol) and potassium hydroxide
(6.56 g, 117 mmol) in water (118 mL), was added a mixture of e (6 mL), potassium
hydroxide (13.2 g, 234 mmol) in water (240 mL) at 0 CC, followed by addition of a solution of
potassium hydroxide (19.8 g, 351 mmol) in water (350 mL). After 5 minutes at 0 CC, the
mixture was heated in a 100 OC oil bath for 1 hr. The reaction solution was cooled to room
temperature, and then, in an ice-water bath for 30 minutes. To the mixture, a solution of HCl
(240 mL, 2N) was added dropwise at 0 CC, and the resulting mixture was kept for 1 hr. The
supsension was d and washed with water (5 mL) to give 2-aminonitro-benzoic acid as
yellow solid (15.6 g, 73% yield): HPLC: Waters Symmetry C18, 5 um, 3.9 x 150 mm, 1 mL/min,
240 nm, CH3CN/O.l% H3PO4, 5% grad to 95% over 5 min, 5.83 min (85%); 1H NMR (DMSO-
d6) 5 6.90 (dd, J: 1, 8 Hz, 1H, Ar), 7.01 (dd, J: 1, 9 Hz, 1H, Ar), 7.31 (t, J: 8 Hz, 1H, Ar),
2012/035429
8.5-9.5 (brs, 3H, OH, NHz); 13C NMR(DMSO-d6)5105.58, 110.14, 120.07, , 149.80,
151.36, 166.30; LCMS: MH = 183.
A mixture of 2-aminonitro-benzoic acid (1.5 g, 8.2 mmol) in acetic anhydride (15 mL)
was heated at 200 0C for 30 minutes in a microwave oven. The mixture was filtered and washed
with ethyl acetate (20 mL). The filtrate was concentrated in vacuo. The solid was stirred in
ether (20 mL) for 2 hrs. The suspension was d and washed with ether (20 mL) to give 2-
methylnitro-benzo[d][1,3]oxazinone as a light brown solid (1.4 g, 85% yield): HPLC:
Waters Symmetry C18, 5um, 3.9 x 150 mm, 1 mL/min, 240 nm, CH3CN/0.l% H3PO4, 5% grad
95% in 5 min, 5.36 min (92%); 1H NMR (DMSO-d6) 5 2.42 (s, 3H, CH3), 7.79 (dd, J: 1, 8 Hz,
1H, Ar), 7.93 (dd, .1: 1, 8 Hz, 1H, Ar), 8.06 (t, .1: 8 Hz, 1H, Ar); 13C NMR (DMSO-d6) 5 20.87,
107.79,121.54,128.87,137.19,147.12,148.46,155.18,161.78;LCMS:MH= 207.
Two vials each with a suspension of omethyl-benzo[d][1,3]oxazinone (0.60 g,
2.91 mmol) and 3-amino-piperidine-2,6-dione hydrogen chloride (0.48 g, 2.91 mmol) in pyridine
(15 mL) were heated at 170 0C for 10 minutes in a microwave oven. The suspension was filtered
and washed with pyridine (5 mL). The filtrate was concentrated in vacuo. The ing mixture
was stirred in HCl (30 mL, 1N), ethyl acetate (15 mL) and ether (15 mL) for 2 hrs. The
sion was filtered and washed with water (30 mL) and ethyl acetate (30 mL) to give a dark
brown solid, which was stirred with methanol (50 mL) at room temperature overnight. The
suspension was filtered and washed with methanol to give 3-(2-methylnitrooxo-4H-
quinazolinyl)-piperidine-2,6-dione as a black solid (490 mg, 27% . The solid was used
in the next step without further purification.
A mixture of 3-(2-methylnitrooxo-4H-quinazolinyl)-piperidine-2,6-dione (250
mg) and Pd(OH)2 on carbon (110 mg) in DMF (40 mL) was shaken under hydrogen (50 psi) for
12 hrs. The sion was filtered through a pad of Celite and washed with DMF (10 mL).
The filtrate was concentrated in vacuo and the resulting oil was d by flash column
chromatography (silica gel, methanol/methylene chloride) to give 3-(5-aminomethyloxo-
4H-quinazolinyl)-piperidine-2,6-dione as a white solid (156 mg, 69% yield): HPLC: Waters
Symmetry C18, 5um, 3.9 x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, 3.52 min
(99.9%); mp: 293-295 0C; 1H NMR (DMSO-d6) 5 2.10-2.17 (m, 1H, CHH), 2.53 (s, 3H, CH3),
2.59-2.69 (m, 2H, CH2), 2.76-2.89 (m, 1H, CHH), 5.14 (dd, J: 6, 11 Hz, 1H, NCH), 6.56 (d, J:
8 Hz, 1H, Ar), 6.59 (d, J: 8 Hz, 1H, Ar), 7.02 (s, 2H, NHZ), 7.36 (t, J: 8 Hz, 1H, Ar), 10.98 (s,
2012/035429
1H, NH); 13C NMR (DMSO-d6) 5 20.98, 23.14, 30.52, 55.92, , 110.48, 111.37, 134.92,
148.17, 150.55, 153.62, , 169.65, 172.57; LCMS: MH = 287; Anal. Calcd. for
C14H14N403 + 0.3 H20: C, 57.65; H, 5.05; N, 19.21. Found: C, 57.50; H, 4.73; N, 19.00.
6.4 Identification of direct compound targets
To identify the direct target of thalidomide and other related drugs, we develop an
affinity purification technique. A compound l (“Compound A”) coupled to Affigel-10 (10
umol drug per mg Affigel) was used for affinity purification experiments.
0 O
HZN/QLM O
Compound A (TNF IC50=622 nM; Jurkat IL-2 EC200=3.47 uM)
Proteins were isolated from Jurkat T cell lysates by binding to the Compound A-Affigel
followed by elution using free Compound A. Coomassie stained bands were excised and sent to
Harvard Microchemistry Facility for sequence analysis. The proteins were proteolytically
digested and analyzed by microcapillary e-phase HPLC nano-electrospray tandem mass
spectrometry on a Finnigan LCQ DECA quadrupole ion trap mass spectrometer. The MS/MS
spectra were correlated with known sequences using the algorithm t and other programs,
then the peptide sequences were reviewed by a scientist for consensus with known proteins and
the s manually ed for fidelity.
Summary afresults: DDBl (DNA damage binding protein 1 (XPCE, human) was affinity
purified from Jurkat extracts using Compound A-immobilized beads. DDBl was highly
represented in the eluted fractions (108 peptides) compare with for example with the second
proteins most represented Glycogen branching enzyme (55 peptides). DDBl ly interacts
with CRBN and could had been pull-down by virtue of its binding to CRBN.
6.5 CRBN siRNAs knocked down CRBN in sensitive multiple
myeloma cell lines
The role of cereblon (CRBN) in lenalidomide MOA was confirmed using knock-down
experiments in two lenalidomide ive multiple myeloma cell lines, H929 and U266B1. It
was found that down regulation of CRBN tes drug-induced cell cycle arrest, activiation of
tumor ssors, inhibition of oncogenes and global changes in gene expression profiles and
ubiquitination.
different single and pool siRNAs against CRBN were evaluated in H929 and U266Bl
cells. RT-PCR was used to test the own efficiency after 24 and 48 hour transfection. The
results showed that the CRBN-siRNA-l, iRNA-7, CRBN-siRNA-9, CRBN-siRNA-IO,
and CRBN-siRNA-ll significantly reduced the expression of CRBN mRNA as ed with
other siRNAs and niock siRNA (Table 1).
Table 1: Effect of CRBN-siRNAs 0n CRBN gene expression
% tion of CRBN mRNA relative to CRBN
mRNA levels in Mock control
siRNA conc
siRNA 10 nM 25 nM 50 nM
lnvitrogen siRNAs
Low GC Neg ctrl 88 / 100 85.5 / 77.5 85 / 77
CRBN-7 22 / 25 14/ 17.5 16.5 / 17
CRBN-8 47.5 / 61 29.5 / 41 33 / 37.5
CRBN-9 67.5 / 66.4 61.5 / 52 42/37
Dharmacon siRNAs
Smart pool neg ctrl 87/ 78 72.5 / 84 98.5 / 88.5
CRBN Smartpool 28 / 34.5 19.3 / 28.5 18/ 17
CRBN-9 55/40 28.5 / 33 17.5 / 23
CRBN-10 23/ 35 20.5 / 29 20 / 22.5
J11 22 / 27 20 / 17 16.3 / 15.3
J12 55/ 53 37/39 21 /25
6.6 Knockdown of CRBN abrogates the anti-proliferative
effect of drugs in multiple myeloma cells
Drugs such as lenalidoniide and idoniide have direct anti-proliferative activity
against MM cells by inducing cell cycle arrest in G1 phase, followed by a decrease in viability.
To study the role of CRBN in lenalidoniide and other drugs anti-proliferative activities, H929
and U266Bl cells, two sensitive myelonia lines, were transfected with CRBN-siRNAs or control
siRNAs for 24, 48, 72 and 96 hours. Cells were treated 24 h after transfection with DMSO
(0.1 %), ponialidoniide (1 uM) and lenalidoniide (lO uM) for l, 2, 3 days to evaluated the
WO 49299 2012/035429
compound effect on CRBN protein, mRNA expression and the effect on cell cycle and
proliferation. RT-PCR and western blot assays showed that CRBN siRNAs knocked down
CRBN. CRBN down regulation was confirmed by RT-PCR and Western blot using the
CRBN70 antibody (Figure 1). Treatment with lenalidomide and pomalidomide affected neither
mRNA nor protein expression of CRBN significantly.
Lenalidomide and pomalidomide induced a delay of cell cycle progression, measured as
the decrease of the number of cells in S phase, of 40 % and 50 % respectively in control mock
and negative control siRNA-transfected cells (average inhibition of 3 days of treatment)
(Figures 2A & 2B). Knockdown of CRBN markedly ted the lenalidomide and
pomalidomide-induced delay in cell cycle progression in U266Bl cells. Id.
The effect of CRBN in H929 cells was also evaluated. H929 cells were transfected with
mock, negative control siRNA and CRBN-siRNA-7 for 24, 48, 72 and 96 h. Cells were treated
24 h after transfection with DMSO (0.l %), pomalidomide (1 uM), lenalidomide (lO uM) or 3-
nomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione ound B”) for l, 2, 3
days and the effect on cell cycle and proliferation investigated. domide, pomalidomide
and Compound B induced a delay of cell cycle progression, ed as the decrease of the
number of cells in S phase, in control mock and negative control siRNA-transfected cells after 72
h treatment (Figure 2C). Knockdown of CRBN markedly abrogated immunomodulatory drugs-
induced delay in cell cycle progression in H929 cells e 2C) from of 50 to 4% for
lenalidomide, from 70 to 15% for pomalidomide, and from 65 to 22% for Compound B.
6.7 Knockdown of CRBN abrogated effect of drugs on cell
cycle, tumor suppressor and apoptotic proteins
To further investigate the effects of CRBN on the cell cycle arrest induced by drugs we
used RT-PCR and Western blot analysis to measure the levels of key cell cycle and apoptotic
tors. U266Bl cells were transfected with mock, negative control siRNA, iRNA-7
and CRBN-siRNA-ll for 24, 48, 72 and 96 h (Figure 3A). Cells were treated 24 h after
transfection with DMSO (0.l %), pomalidomide (1 uM) and lenalidomide (lO uM) for l, 2, 3
days and the effect on mRNA and protein levels of the cyclin-dependent kinase (CDK) inhibitor
p2lWAF'1 were evaluated. It has been shown that lenalidomide- and pomalidomide-induced cell
cycle arrest is dependent on up-regulation of p2lWAF'1 in U2669. Our results showed that p21
was up-regulated by lenalidomide and pomalidomide in control mock and negative control
WO 49299
siRNA-transfected cells (Figure 3C) indicating a decrease of S phase cells resulted from
domide and pomalidomide Gl arrest (Figure 3B). However, knockdown of CRBN
prevents the induction of p2lWAF'1 indicating the successful abrogation of G1 arrest and renewal
of S phase ssion (Figure 3C & 3D).
In H929 cells, the cell cycle arrest in G1 phase by the drugs coincides with a reduction of
tumor suppressor, pr, phosphorylation and the oncogene and myeloma survival factor IRF4.
n blot analysis showed that lenalidomide, pomalidomide and nd B decreased
phosphorylation ofpRB (Figures 4A & 4B) and total level of protein IRF4 (Figures 4C & 4D).
The effect of the drugs was reduced by knockdown of CRBN suggesting that inhibition of cell
cycle progression by the drugs requires CRBN protein.
6.8 Knockdown of CRBN inhibits lenalidornide and domide
effects on gene expression
Gene expression profile using microarray technology identified 759 or 609 genes
differentially modulated in negative control siRNA-transfected U266Bl cells treated with
pomalidomide (1 uM) or domide (lO uM) compared to DMSO treated control (:: 17 fold;
P<0.05 ANOVA e) (Figures 5A & 5B).
Representative significant Gene Ontology (GO) classes of down regulated genes in
domide include: cell cycle (87 genes; P = 5.2E-56), mitosis (43 genes; P = l.2E-39),
cytoskeleton (58 genes; P = 2.6E-l6) and response to DNA damage stimulus (36 genes; P =
l.8E-2l). Representative significant Gene Ontology (GO) classes of up regulated genes include:
antigen processing and presentation (12 genes; P = 2.8E-l7), immune response (35 genes; P =
.70E-l4) and cell death (50 genes; P = l.7E-lO).
Representative significant Gene Ontology (GO) classes of up regulated genes in
lenalidomide include: antigen processing and presentation (ll genes; P = l.9E-l6), immune
response (37 genes; P = 3.9E-l3) and cell death (55 genes; P = l.0E-lO) (Tables 4 and 5).
domide and pomalidomide s on cell cycle and gene expression s in U266 were
abrogated by knockdown of CRBN using 4 different siRNAs (Figures 5A — 5C).
6.9 CRBN levels are decreased in multiple a cells resistant to
domide 0r pomalidomide
Although the development of lenalidomide-based therapies has improved significantly
clinical responses, most multiple myeloma patients ally relapse or become tory to
their therapeutic regimens. Multiple myeloma cell lines resistant to the anti-proliferative s
of lenalidomide have been developed in order to evaluate the potential mechanisms responsible
for lenalidomide resistance.
Due to the relevance of CRBN for the roliferative response of lenalidomide,
pomalidomide and other immunomodulatory the levels of CRBN protein was compared in
matched pairs of parental sensitive lines with acquired lenalidomide- or pomalidomide-resistance
cells. Consistent with CRBN being required for the anti-proliferative activity of lenalidomide
and pomalidomide, the levels of CRBN n were significantly lower in the domide-
resistant cells line DF15R and the lenalidomide-resistant cells, H929 RlO-l, H929 RlO-2, H929
RlO-3, H929 RlO-4 and MMl/R compared to the matched parental lines (Table 2).
Table 2. Fold difference of CRBN protein level between lenalidomide-
or pomalidomide-resistant cells and the d parental cells
CRBN protein fold
decrease relative to
matched al lines
DF15R 7.16E-07
H929 R10-1 0.503989
H929 R10-2 0.295482
H929 R10-3 0.459599
H929 R10-4 0.659341
MM1/R 0.172249
6.10 Genomic DNA sequencing of CRBN, DDBl and GSK3 from
human cell lines and primary cells
The target genes CRBN, DDB l and GSK3B were sequenced from a variety of human
cell lines and primary cells. Sequencing of the CRBN gene identified mutations in lenalidomide
resistant human cell lines which are absent in parental cells.
Sequence enrichment, NeXGen sequencing, and data analysis yielded the results shown in
Tables 3-6 below. Each table lists the cell lines from which the data are derived. The reference
nucleotide refers to the wild type nucleotide at that position. “Coverage” refers to the total
number of reads at that position. The l mutation score (“Score”) is based on the concept of
Phred scores with a maximum value of 30, meaning the ility that the mutations call is
wrong is 1/1000; 20, 1/ 100; and 10, 1/ 10. A Score, however, does not necessarily mean that the
mutation is more than likely a false mutation. A low Score s only that the mutation cannot
be called a true mutation with absolute certainty. “Mutation Call” denotes the nucleotide change.
For example, T > TG indicates a heterozygous change from reference T to T and G. T > G
indicates a homozygous change from reference T to G. The term “c.” refers to the coding
sequence while “IVS” refers to an intron variant. The “Amino Acid Change” column uses
similar notation to the “Mutation Call” column.
Results
In the large-scale sequence analysis of 27 cell lines, more intronic mutations were found
than exonic mutations. The le myeloma cell line, ANBL-6, showed a mutation in CRBN
of the lenalidomide-resistant line that was not seen in the wild type. ANBL-6.wt was d
only with DMSO and the CRBN coding sequence exactly matched the reference. However, in
the ANBL-6.R10R which has resistance to 10 uM lenalidomide, a SNP in the coding region
c.745C>CA caused an amino acid change 249D>YD in the protein. This amino acid change
mapped to the DDB1 binding domain of CRBN.
A silent mutation found in the CRBN coding region of HepG2 and JeKo-l was
heterozygous c.735A>AG with KMS-lZ-BM as homozygous c.735A>G. The cell line, OPM2,
had a different silent mutation in the coding region of CRBN, c.1209C>CT. No amino acid
changes resulted from these SNPs.
The sequencing results for DDB1 uncovered a SNP in the coding region >TA
which resulted in an amino acid change D in both .wt and ANBL-6.R10R cell
lines. A different SNP was found in the Jurkat cell line, with a mutation c.2143C>CT in the
DDB1 coding region that changed the amino acid sequence 715V>VI.
A silent mutation found in the DDB1 coding region of ANBL-6.wt, ANBL-6.R10R, and
SH-SYSY at c.153G>GA did not change the amino acid sequence. A sample ofPBMC from a
healthy donor also had a silent mutation in the DDB1 coding region c.2265G>GA that did not
change the amino acid sequence.
One GSK3B mutation was found in the PMBC sample. The on in the coding
region c.1187C>CT ed in an amino acid change 396R>RQ. This mutation did not map to
the kinase domain. Other mutations are shown in Table 11. Most of these have low coverage.
This could be due to primers targeting these regions and/or sequencing error.
While no consistent mutations in CRBN, DDBl and GSK3-B were found to correlate
with resistance to lenalidomide or pomalidomide in these MM cell lines, sporadic mutations such
as the 249D>YD CRBN on observed in lenalidomide-resistant ANBL-6 MM cells
exemplify the type of polymorphism which might occur in such genes within the clinical g,
and which might constitute a mechanism of resistance. Further studies would be needed to
confirm or refute this hypothesis.
Table 3 CRBN ons
Amino Acid
Cell line Mutation Call Change
OPMZ c.1209C>CT 403T>TTa
HepGZ >AG 245Y>YYa
JeKo-1 c.735A>AG 245Y>YYa
KMSBM c.735A>G 245Y>Ya
ANBL-6.R10R c.745C>AC 249D>YDb
ws-lz-BM
SKMMZ |VSll48+21_1148+22insA
EJM IVS1329+18_1329+19insAACT
H929_R10-4 |VSl329+18 1329+19insAACT
JJN-3 |VSl329+18_1329+19insAACT
OPMZ |VSl329+18_1329+19insAACT
SH-SY5Y 9+18_1329+19insAACT
MM.1S.R10R |VSl75-9A>AG
MM.1S.Wt |VSl75-9A>AG
PBMC |VSl75-9A>AG
HepGZ |VSl75-9A>AG, |VSll48+21_1148+22insA
ANBL-6.Wt |VSl75-9A>G
EJM |VSl75-9A>G
H929_D1 lVSl75-9A>G —
H929_R10-1 |VSl75-9A>G
H929_R10-2 |VSl75-9A>G
H929_R10-3 |VSl75-9A>G
H929_R10-4 lVSl75-9A>G —
H929-1uMCC5013
|VSl75-9A>G
—IV5175-9A>G —
JJN-3 |VSl75-9A>G —
-—-KMS-lZ-BM |VSl75-9A>G
-—-RPMI-8226 |VSl75-9A>G
SK-Hepl |VSl75-9A>G —
SKMMZ |VSl75-9A>G —
——ANBL-6.R10R -9A>G |V51148+21 1148+22insA
-|V5175-9A>G|V51148+21 1148+22insAI |V5528-29 528-
U87 28insCT
H929 |V5175-9A>GI 9+18 1329+19insAACT
H929-0.1uMCC4047
|VSl75-9A>G, |VSl329+18_1329+19insAACT
H929-DMSO -9A>G, |V5528-29_528-28insCT
KMS-lZ-BM |V5528-29_528-28insCT —
SKMMZ |V5528-29_528-28insCT —
U266_Bl Ivs528-29 528-28insCT _
a = silent mutation; b = region required for DDBl interaction
Table 4 DDBl Mutations
Amino Acid
Cell line Mutation Call Change
ANBL-6.R10R C.153G>AG 51P>PPa
ANBL-6.wt C.153G>AG 51P>PPa
Y C.153G>AG 51P>PPa
Jurkat C.2143C>CT |
PBMC c.22656>AG 755$>SSa
ANBL-6.R10R C.909T>AT 303 E>DE
ANBL-6.Wt C.909T>AT 303 E>DE
ANBL-6.Wt |V51123-29A>G
EJM |V51123-29A>G
H929 |V51123-29A>G
-3 3-29A>G
H929-1uM-
CC5013 |V51123-29A>G
HepGZ |V51123-29A>G
—Ivs1123—29A>G
MM.1S.wt |V51123-29A>G
OPM2 |V51123-29A>G
SK-Hepl |V51123-29A>G
U266_Bl |V51123-29A>G
EJM |VSllZ3-30C>T
H929 M
H929_R10-3 M
H929-1uMCC5013
|VSllZ3-30C>T
HepGZ |VSllZ3-30C>T
JeKo-l |VSllZ3-30C>T
MM.1S.wt |VSllZ3-30C>T
OPM2 |VSllZ3-30C>T
SK-Hepl |VSllZ3-30C>T
l 3-30C>T
PBMC |V51225+30T>C
MM.1S.R10R |V51225+30T>CT
MM.1S.wt
RPMI-8226 |V51225+30T>CT
JJN-3
OPMZ
H929-0.1uM-
CC4047 |VSl862-27A>AC
JJN-3 |VSl862-27A>AC
OPMZ 2-27A>AC
SH-SY5Y |VSl862-27A>AC
H929 |V52278-26T>GT
H929-1uM-
CC5013 |V52278-26T>GT
Jurkat |V52278-26T>GT
KMS-lZ-BM |V52278-26T>GT
OPM2 |V52278-26T>GT
ANBL-6.wt |V52278-27C>CT
EJM |V52278-27C>CT
H929 |V52278-27C>CT
H929_R10-2 |V52278-27C>CT
CC5013 |V52278-27C>CT
JJN-3 |V52278-27C>CT
Jurkat |V52278-27C>CT
-BM |V52278-27C>CT
OPMZ |V52278-27C>CT
PBMC |V52278-27C>CT
SK-Hepl IVSZZ78-27C>CT
U266_Bl IVSZZ78-27C>CT
ANBL-6.wt |V52278-28C>T
H929 |V52278-28C>T
-3 |V52278-28C>T
CC5013 |V52278-28C>T
Jurkat |V52278-28C>T
KMS-lZ-BM |V52278-28C>T
OPMZ |V52278-28C>T
SH-SY5Y |V52278-28C>T
U266_Bl |V52278-28C>T
JJN-3 |V52661+6C>CT
PBMC IVSZ832+6C>CT
RPMI-8226 IVSZ832+6C>CT
a = silent mutation
Tables GSK3|3 ons
Amino Acid
Cell line Mutation Call Change
PBMC c.1187C>CT 396R>RQ
+3de|T —
U266_Bl I—VS366+29A>AG —
H929 I—VS366+29A>G
Jurkat IVS909+11de|A
Table 6 Other Mutations
Chr Y: LOC100288025
Chr M: ATP6, COXI, CYTB,ND1,ND4,ND4L,ND5
Chr 2: C20rf67
Chr 1
Chr 19: KLKlO
Chr 17: KRTlS
Chr 14: PRMTS, FMNLl
Chr 9: NOTCHl
6.11 Study of the relationship between drugs and the ubiquitin
proteasome system
Specific antibodies for poly-ubiquitin chains were used to study the effect of
immunomodulatory drugs on global levels of ubiquitination. H929 cells were d with
lenalidornide (1 uM), pornalidomide (1 uM) or proteasorne inhibitor MG132. After 30 minutes
cells were process for immunofiuorescence. Global levels of K63-linked iquitination
were quantified by Cellornics. As shown in Figures 7A & 7B, immunomodulatory drugs
decrease total K48-linked polyubiquitination but not Klinked ubiquitination in H929.
6.12 Study of the effect of drugs on global changes of ubiquination
and protein abundance
The effects of lenalidornide and pornalidomide on protein ubiquination were investigated
using CST Ubiscan technology. Treated samples were sent to Cell Signaling Technology for
nated peptide enrichment and quantification by LC/MS/MS. Raw intensity was used for
this analysis to identify peptides that are significantly regulated by the drugs, or the drugs with
sorne inhibitor MG132. Analysis showed that compared with MG132, the effects of
lenalidornide and pornalidomide on ubiquitinated es are small. In the MG132 combo,
more ubiquinated peptides are observed (compared with their controls). 162 unique
ubiquitinated peptides were significantly up-regulated by lenalidornide and pornalidomide alone,
or with MG132 at 1 hour or 4 hours. These peptides correspond to 176 unique ns. Top
few groups are: nucleosome, chromatin, protein-DNA complex ly, Histone H2A. Among
the 176 proteins, we found five proteins that belong to "ubiquitin-protein ligase ty"
category, they are MDMZ, HERCZ, UBE2D3 (only by idomide), UBE2N (lenalidornide
only), UBEZM (both). Results for hits categorized by conditions are shown in Figures 8 & 9
(without MG132) and Figures 10 & 11 (with MG132).
6.13 CRBN knockdown effect on drug induced TNFoL and IL-2 in
primary T-cells
In these studies, human T cells were isolated from blood and d with lug/ml PHA-L
at 37°C. After 24 hr stimulation T cells were subjected to siRNA ection with the indicated
siRNAs. Knockdown efficiencies were analyzed by qRT-PCR after 24 h transfections and the
remaining transfected cells seeded in 96-well plate s pre-bound with OKT3 and treated with
DMSO or 1 and 10 uM thalidomide, domide, pomalidomide and phthalimide in duplicate
at 37°C for 48 hours. After 48 hours, the supematants were collected and tested for TNFot and
IL-2 production by ELISA (Figures l2A — 12D). This data indicates that siRNA knockdown of
CRBN abrogates drug-induced TNFu and IL-2 production in anti-CD3-stimulated primary
human T cells.
6.14 Knocking down Cul4A and Cul4B together lly abrogates
domide, pomalidomide, 0r nd B—induced TNFa and
IL-2 induction in T cells
Cul4A knockdown efficiency prior to drug treatment was measured. Cul4A gene
expression was knocked down by 82% and 76% by Cul4A siRNA-l and Cul4A + Cul4B siRNA,
respectively (Figure l3A). Cul4B gene expression was suppressed by 70% and 63% byCul4B
and Cul4A + Cul4B siRNA, respectively. The dual knock down of Cul4A or Cul4B had
no effect on T cell TNF-(x or IL-2 production induced by 10 uM lenalidomide, pomalidomide or
Compound B (Figures 13 B & C). However, the double knockdown of Cul4A and Cul4B
together resulted in a significant but partial reversal of the compound-induced elevation of TNF-
production due to lenalidomide, pomalidomide, and Compound B (Figure l3B). There was a
trend of a reversal of IL-2 ion when Cul4A and Cul4B were knocked down e l3C).
These data suggest that lenalidomide, pomalidomide, and Compound B-mediated T cell
costiulation is dependent on the expression of Cul4A and Cul4B, and that these proteins serve
redundant functions in the T cell.
6.15 CRBN expression and sensitivity to lenalidomide in lymphoma
cells
The antiproliferative ty of lenalidomide versus baseline CRBN expression was
studied in diffuse large B-cell lymphoma (DLBCL) cell lines. The ing DLBCL cell lines
were evaluated for sensitivity to lenalidomide: e-NCI, U2932, OCI-Ly-3, DB, RIVA,
TMD8, Toledo, OCI-Ly-l9, Pfeiffer, WSU-DLCL2, Karpas-l lO6P and SU-DHL-4. Results are
shown in Figure 14.
6.16 Preparation of DBI x
Primers were designed for g of CRBN into pBV-ZZ-HT-LIC and pBV-notag-LIC.
Two primers were prepared, “CRBN_For” and ev.”
CRBN_F0r: GTGCCGCGTGGCTCCATGATGGCCGGCGAAGGAGATCA
CRBN_Rev: TTTCGGGCTTATTACAAGCAAAGTATTACTT
The primers were used to amplify the CRBN gene from a cDNA library. The product
was gel purified and treated with T4 DNA polymerase in the presence of TTP only to make
single-stranded ends compatible for ligation independent cloning. The CRBN DNA was then
annealed to pBV-ZZ-HT-LIC to create CRBN_034 (Figure 15A).
For DDB l two primers were prepared, “DDBl_F0r” and “DDBl_Rev.”
DDBl_F01‘: TCGGGCGCGGCTCTCGGTCCGAAAAGGATGTCGTACAACTACGTGGTAAC
(SEQ ID NO:2)
DDB 1_Rev:
TTTCGGGCTTATTTTTCGAACTGCGGGTGGCTCCAATGGATCCGAGTTAGCTCCT
(SEQ ID N03)
The DDBl_Rev adds a StrepTag at the C-termini of DDBl. The DDBl gene was
amplified from a cDNA library, gel purified, and treated with T4 polymerase in the presence of
TTP. The DDBl gene was then annealed to pBV-notag-LIC to create the plasmid DDB l_004
(Figure 15B).
Expression ofconstructs in baculovz'rus andpurification
The constructs could were tested for expression in insect cells. Recombinants pBV-HT-
LIC and pBV-GST-LIC plasmids were transformed into DHlOBac to ed s.
Integrity of the recombination was followed by a blue-white screen and PCR. The recombinant
bacmids were used to transfect 9 x 105 Sf9 adherent cells per well in serum free-Grace media.
After the transfection, fresh Grace media containing antibiotics and glutamine was added.
Infection was followed by observation of the cell monolayers under microscope. After 5
to 7 days, the supematants were saved (Pl virus) and the s were analyzed for recombinant
protein expression. Virus amplification was in 24 deep well plates with 4 ml of 2 x 106 Sf9
cells/ml per well. Aliquots were removed to assess the kinetics of protein expression. After 4
days, the plate was centrifuged, the supernatant were saved (P2 virus) and the pellets were
ed by mini scale purification of the tagged proteins. The viruses were finally amplified in
2012/035429
750 ml of Grace media containing antibiotics and glutamine and the supernatants saved as P3
virus. Pellets were saved and d using either the AKATxpress or the AKTA purifier from
Amersham Biosciences.
Purification
Cell pastes containing CRBN-DDBlwere lysed in a buffer containing 50 mM Tris pH 8.0,
500 mM NaCl, 20 mM Imidazole, 10% Glycerol, and 2 mM DTT and se inhibitors. The
lysate was then cleared by centrifilgation. The tagged proteins were then d from the
supernatants using the AKTA Express from Amersham Biosciences. Five ml p HP
columns were used for the affinity step while a 16 mm X 60 cm Sephacryl S-200 HR was used
for the size exclusion steps. After loading the column, was column was washed with 20 volumes
of lysis buffer, then 10 column volumes of 50 mM Tris pH 8.0, 1000 mM NaCl, 40 mM
Imidazole, 10% Glycerol, and 2 mM DTT. Elution of the bound proteins was performed with
lysis buffer containing 500 mM Imidazole. Eluted proteins were directly injected into the gel
filtration column equilibrated in 25 mM Tris pH 8.0, 200 mM NaCl, 5 % ol, and 2 mM
DTT. Fractions were analyzed by 4-20 % SDS rylamide gel electrophoresis.
Fractions containing both CRBN and DDBl were pooled and digested with Thrombin to
remove the ZZ-HT tag from CRBN. Digestion was carried at 4°C for 5-6 hours with 12000
t/weight) of thrombin and CRBN-DDBl. Cleaved CRBN-DDBl was diluted in 25 mM
Tris pH 8.0, 5 % Glycerol, and 2 mM DTT, and loaded onto an 8 ml MonoQ column
(Amersham-Pharmacia) equilibrated in 25 mM Tris pH 8.0, 75 mM NaCL, 5% ol, and 2
mM DTT. After loading the column was wash with 2 volumes of 25 mM Tris pH 8.0, 75 mM
NaCl, 5 % Glycerol and 2 mM DTT, and the bound proteins were eluted with a gradient from 75
mM to 400 mM in 25 mM Tris pH 8.0, 5 % Glycerol and 2 mM DTT
A final gel filtration was done to polish the CRBN-DDBl complex. The fraction pooled
from the MonoQ were loaded onto a 140 ml S200HR Gel filtration column and ran in 25 mM
Tris pH 8.0, 200 mM NaC, 5 % Glycerol, and 2 mM DTT. Fractions were analyzed and positive
fractions were pooled and concentrated to approximately 15 mg/ml. Aliquots were stored at -
80°C.
6.17 Ubiscan ubiquitination experiments
The results of 1 hour and 4 hour ubiquitination experiments are shown in Figures 17-22,
which demonstrate that certain es are regulated by lenalidomide and/or pomalidomide.
WO 49299
The tables of Figure 23 show Ubiscan data results for lenalidomide, pomalidomide and
Compound B. teins IKZF3, RPL19, PCMl and NEDD8 were commonly increased in
abundance by ReV and Pom in U266 and Compound B in T cells. Proteins GNB2L1 and
HNRNPR were commonly decreased in abundance by ReV and Pom in U266 and Compound B
in T cells.
Treatment of T cells with Compound B resulted in a greater abundance of two
ubiquinated peptides (vs. DMSO control), SECTMl and .
Proteins in common with lenalidomide, pomalidomide and Compound B: IKZF3, RPL19,
PCMl, NEDD8, GNB2Ll, and HNRNPR.
Table 7 Final Ubiscan hits for lenalidomide and pomalidomide (1hr)
ID Gene Name Pe tide Se uence
1 147 G3BP2 NK*APEYLHR
2 904 COPS6 QVCEIIESPLFLK*LNPM#TK
3 905 COPS6 QVCEIIESPLFLKLNPM#TK"<
1 137 VCPIP 1 VGDVQGQESESQLPTKIILTGQK"<
9 15 82 HYOU1 FFGDSAASM#AIK*NPK
2541 MCM7 FLQEFYQDDELGK*K
13 3043 CCT3 SM#M#K*MLLDPMGGIVM#TNDGNAILR
14 3226 LMNB2 LSSDQNDK*AASAAR 278
16 3910 C 12orf5 1 LSPYLEDVSGGMWPVVHIQK*KNTK
18 3992 EDEM3 ATGDPYYLEVGK*TLIENLNK
4982 RAB28 VVK*ADIVNYNQEPM#SR
33 7093 L 1 SCSTQLGEEPFSYGYGGTGK*K
7556 ABCF2 YGLTGK*QQVSPIR
37 7740 DNAJC 1 ALPHLIQDAGQFYAKYK*
3 8 7798 GNAS VLTSGIFETKFQVDK*VNFHM#FDVGGQRD
39 8193 SLC16A1 ASLEK*AGK
42 10418 RPL19 HMGIGK*R
43 10556 RPL36 AMELLKVSK*
44 10565 RPL4 MFAPTK*TWR
46 11831 UBE2Q1 ELK*LLESIFHR
47 12009 ARMC6 NLVAHGQAFSK*PILDLGAEALIM#QAR
50 12698 KLHL7 ISVNSNNVQSLLDAANQYQIEPVK*K
51 12891 NUP37 FCTSAADMK*IR
52 12942 POC5 VVTSAQQK*AGR
54 13152 SNRPE IM#LK"<GDNITLLQSVSN
2012/035429
PAGE INTENTIONALLY LEFT BLANK
Table 8 Final Ubiscan hits for lenalidomide and pomalidomide (MG 1hr)
ID Gene Name Petide Se uence
KS K*ASSKGPK
N 324 SHCBP1 AYQDYILADCK*ASEVQEFTAEFLEK
3 89 YWHAE MK*GDYHR
512 FERMT3 ETTLSYYK*SQDEAPGDPIQQLNLK
904 COPS6 QVCEIIESPLFLK*LNPM#TK
905 COPS6 QVCEIIESPLFLKLNPM#TK*
1010 PCM1 LMAAK*QK
9 1 1 12 SMC4 SVAVNPK*EIASK
1 1 14 TOPORS K*IQEQDIINFR
1 1 1323 HSPA1A SAVEDEGLK*GK
12 1323 HSPA1B SAVEDEGLK*GK
13 1452 HSPA8 DISENK*R
14 1623 ATRX DNRGGIKSK*
1679 DUT IFYPEIEEVQALDDTERGSGGFGSTGK*N
16 1773 H2AFJ K*GNYAER
17 1773 2 17
18 1773 HIST1H2 K*G\YAER
19 1773 HIST1H2 K*G\YAER
1773 HIST1H2 ER
21 1773 HIST2H2 K*G\YAER
22 1773 2 K*G\YAER
23 1773 HIST2H2 K*G\YAER
24 1863 H2AFX K*TSATVGPK
3146 LMNA TLEGELHDLRGQVAK*LEAALGEAK
26 3192 LMNA K*LESTESR
27 3377 TUBA1A DVNAAIATIK*TK
28 3377 TUBA1B DVNAAIATIK*TK
29 3377 TUBA1C DVNAAIATIK*TK
3377 TUBA3C DVNAAIATIK*TK
31 3377 TUBA3D DVNAAIATIK*TK
32 3377 TUBA3E DVNAAIATIK*TK
33 3963 DHFR LTEQPELANK*VDM#VWIVGGSSVYK
34 3984 DHX15 EVDDLGPEVGDIK*IIPLYSTLPPQQQQR
37 41 1 1 GBA LLLPHWAK*VVLTDPEAAK
41 4199 IDH3G NTGK*SIANK
2012/035429
43 4471 PPAT CGLPYVEVLCK*NR
44 4938 GNB3 GQQK*TV
45 4938 HZAFZ GQQK*TV
46 5121 VAVI VLK*YHLLLQELVK
47 5121 VAV3 VLK*YHLLLQELVK
48 5126 VAV1 IDGELK*ITSVER
49 5252 UCK2 VLTSEQKAK*
50 5377 ALDOA ADDGRPFPQVIK*SK
54 5582 SDHA AFGGQSLKFGK*
59 6046 PSMA7 AITVFSPDGHLFQVEYAQEAVK*K
60 6046 PSMA8 AITVFSPDGHLFQVEYAQEAVK*K
61 6049 PSMA7 AITVFSPDGHLFQVEYAQEAVKK*
62 6049 PSMA8 AITVFSPDGHLFQVEYAQEAVKK*
64 6567 IRAKZ CPIPAFPDSVK*PEKPLAASVR
65 6662 PRKDC NILEESLCELVAKQLK*
66 6662 LOC73175 NILEESLCELVAKQLK"<
67 6741 PRKDC GHDEREHPFLVK*GGEDLR
68 6741 LOC73175 GHDEREHPFLVK*GGEDLR
70 7093 HNRNPU IGWSLDSCSTQLGEEPFSYGYGGTGK*K
72 7306 PCBP2 LVVPASQCGSLIGK*GGCK
75 7542 ABCEI VAETANEEEVKK*
78 7783 GNAL VLAGK*SK
79 7783 GNAS SK
80 7939 KCNAB2 IGVGAM#TWSPLACGIVSGK*YDSGIPPYSR
81 8156 PTCHI DKPIDISQLTK*QR
82 8173 SEMA4A VGGEK
84 8478 ASCC3 NCK*K
85 8779 HMGB2 IK*SEHPGLSIGDTAK
86 8808 IF116 KK*EVDATSPAPSTSSTVK
88 8973 ILF2 K*ILGQEGDASYLASEISTWDGVIVTPSEK
89 9023 IRF4 QWLIDQIDSGK*YPGLVWENEEK
91 9082 NACA NILFVITKPDVYK*SPASDTYIVFGEAK
92 9465 SUPTSH SSVGETVYGGSDELSDDITQQQLLPGVK*DPNLWTVK
93 9525 TRIP4 GK*DVEFPNDYPSGCLLGCVDLIDCLSQK
94 9764 EEF 1A1 IGYNPDTVAFVPISGWNGDNM#LEPSANM#PWFK*GW
95 9764 eEF 1AL3 IGYNPDTVAFVPISGWNGDNM#LEPSANM#PWFK"<GW
96 9766 EEF 1A1 IGYNPDTVAFVPISGWNGDNM#LEPSANM#PWFKGW
97 9766 eEF 1AL3 IGYNPDTVAFVPISGWNGDNM#LEPSANM#PWFKGW
99 9794 eEF 1AL3 AAGAGK*VTK
111 11082 RPS25 LVSK*HR
112 11397 COPS3 LKAM#DQEITVNPQFVQK*SM#GSQEDDSGNKPSSYS
1 13 1 1426 CUL9 ILK*AHGEK
1 15 1 1794 UBAP2L IDLAVLLGK*TPSTMENDSSNLDPSQAPSLAQPLVFSN
125 12609 IGJ DLCK*K
126 12627 IKZF3 SHTVEKPYK*CEFCGR
131 13060 S 100A6 EGDKHTLSK*K
132 13212 SSR2 KYDTPK*TK
133 13250 SSX1 SK*AFDDIATYFSK
134 13306 TIPRL LK*VVPTTDHIDTEKLK
136 13598 AMBRAl REPFAVVK*TASEM#ER
137 13676 COPG ALQQYTLEPSEKPFDLK"<SVPLATAPM#AEQR
138 13280 TBCC GK*DAASSTKVDAAPGIPPAVESIQDSPLPK
139 13281 TBCC GKDAASSTK*VDAAPGIPPAVESIQDSPLPK
Table 9 Final Ubiscan hits for lenalidomide and pomalidomide (4hr)
ID Gene Name Pe n tide Se uence
236 GNB2L1 LK*TNHIGHTGYLNTVTVSPDGSLCASGGK
487 CTNNB1 HWPLIK*ATVGLIR
512 FERMT3 ETTLSYYK*SQDEAPGDPIQQLNLK
663 PKP2 TYDMLK*AGTTATYEGR
732 HSP90B1 NLGTIAK*SGTSEFLNK
1 1 12 SMC4 SVAVNPK*EIASK
1 863 HZAFX K*TSATVGPK
2508 HIST2H2AB KTESHKPGK*NK
2512 HIST2H2AB KTESHKPGKNK*
2579 NAP1L2 GLIGYVLDTDFVESLPVKVK*
3712 TPD52 SFEEK*VENLK
3742 VAPA RYCVRPNSGIIDPGSTVTVSVM#LQPFDYDPNEKSK*
3799 AKR1B1 LLLNNGAK*M#PILGLGTWK
3916 CHPF PVRDPVHMYQLHK*AFAR
3955 DDX24 ATNEGLSLM#LIGPEDVINFKK*
4035 FASN DGLLENQTPEFFQDVCKPK*
4181 HMOXI K*AALEQDLAFWYGPR
4347 NANS QLLPCEMACNEK*LGK
4938 GNB3 GQQK*TV
4938 H2AFZ GQQK*TV
4968 NETl IGEATK*PDGTVEQIGHILVSWLPR
5672 ANP32E KLELSDNIISGGLEVLAEK*CPNLTYLNLSGNK
5676 CDC25C SLNQYPALYYPELYILK*GGYR
5732 PPPICB AK*YQYGGLNSGRPVTPPR
6543 CHEK1 M#CGTLPYVAPELLK*R
6546 CSNKIAI LFLIDFGLAK*K
6546 CSNKIAIL LFLIDFGLAK*K
6563 IRAKI GTLAYLPEEYIK*TGR
6843 PRKAGZ KK*DVSSPGGSGGK*K*NASQK*
6858 CPSF3L VNCYM#PANGETVTLPTSPSIPVGISLGLLK*R
7344 RARS YDTSDLAAIK*QR
7672 C7orf42 QSNPEFCPEK*VALAEA
7717 CPNEl SEVIK*NNLNPTWK
8137 NUP88 IYSLREPQTPTNVIILSEAEEESLVLNK*GR
8331 TCIRGI QEENK*AGLLDLPDASVNGWSSDEEK
8723 FAFI K*SPM#M#PENAENEGDALLQFTAEFSSR
8734 FUBP3 ITGDAFK*VQQAR
9253 PSMC3 LAGPQLVQM#FIGDGAK*LVR
9526 TSG101 ASLISAVSDK*LR
9794 EEF1A1 AAGAGK*VTK
9794 3 AAGAGK*VTK
9933 EIF2S1 ADIEVACYGYEGIDAVK*EALR
10690 RPL9 K*FLDGIYVSEK
11010 RPS2 AEDK*EWMPVTK
11010 LOC645018 AEDK*EWMPVTK
11585 NAEI CINITK*QTPSFWILAR
11831 UBE2Q1 ELK*LLESIFHR
12110 C130rf40 KPDLRIIEQEEK*
12242 COMMD4 LEVAAAPGTPAQPVAM#SLSADK*FQVLLAELK
12320 DDIT4 CVEQGK*SCHSVGQLALDPSLVPTF
12458 FAM60A TPVFSFLDLTYWK*R
12545 HLA-E GYEQFAYDGK*DYLTLNEDLR
12758 MAGEA3 AREPVTK*AEM#LGSVVGNWQYFFPVIFSK
12758 MAGEA6 K*AEM#LGSVVGNWQYFFPVIFSK
12865 NHP2 IK*ADPDGPEAQAEACSGER
13290 TBL3 LWTIK*NNECVR
13930 NEDD8 QMNDEK*TAADYK
403 YWHAZ YLAEVAAGDDK*K
805 SHISAS SQPPYNPAYM#DAPK*AAL
2089 HIST1H1A GTLVQTK*GTGASGSFK
2089 HIST1H1B GTLVQTK*GTGASGSFK
2012/035429
84 2089 HISTIHIC GTLVQTK*GTGASGSFK
85 2089 lD GTLVQTK*GTGASGSFK
86 2089 HISTlHlE GTLVQTK*GTGASGSFK
87 13902 NEDD8 LIYSGK*QMNDEK
88 14057 RPS27A K*IQDK*EGIPPDQQR
89 14057 RPS27AP5 K*IQDK*EGIPPDQQR
90 14057 UBA52 K*IQDK*EGIPPDQQR
91 14057 UBB K*IQDK*EGIPPDQQR
92 14057 UBC K*IQDK*EGIPPDQQR
Table 10 Final n hits for lenalidomide and pomalidomide (MG 4hr)
ID Gene Name Peptide Site
PLAA FIIDNTK*GQM#LGLGNPSFSDPFTGGGR
HGS ACGQIFCGK*CSSK
HGS ACGQIFCGKCSSK*
UBE2M VGQGYPHDPPK*VK
UBE2M VGQGYPHDPPKVK*
IL32 GDK*EELTPQK
ANXA7 FGTDEQAIVDVVANR
CP110 NKMLGTSSKESEELLK*SK*
SMC4 SVAVNPK*EIASK
ANP32B IFGGLDM#LAEKLPNLTHLNLSGNKLK*
NAP1L2 GLIGYVLDTDFVESLPVKVK*
PURA FFFDVGSNK*YGVFM#R
VCP KAFEEAEK*NAPAIIFIDELDAIAPKR
VCP ELQELVQYPVEHPDKFLK*
ACTB DIK*EKLCYVALDFEQEMATAASSSSLEK
ACTGI DIK*EKLCYVALDFEQEMATAASSSSLEK
POTEE DIK*EKLCYVALDFEQEMATAASSSSLEK
LSPl QEM#LLSLK*PSEAPELDEDEGFGDWSQRPEQR
NES TSLSFQDPK*LELQFPR
AUPl FPSSGPVTPQPTALTFAK*SSWAR
MANlAl GYAWGLNELK*PISK
MANlAl K*GSGPAALR
TPD52 SFEEK*VENLK
VAPA YCVRPNSGIIDPGSTVTVSVM#LQPFDYDPNEK*SK
PPIA VSFELFADK*VPK
TPIl ELASQPDVDGFLVGGASLK*PEFVDIINAKQ
TPIl KQSLGELIGTLNAAK*VPADTEVVCAPPTAYIDFAR
GNB3 GQQK*TV
H2AFZ GQQK*TV
ALDOA VDK*GVVPLAGTNGETTTQGLDGLSER
MTXl K*VHKISNPWQSPSGTLPALR
PTRH2 TQIAPGSQTVLGIGPGPADLIDKVTGHLK*LY
MYL6 VFDK*EGNGTVMGAEIR
PPP3CA HLTEYFTFK*QECK
PPP3CB HLTEYFTFK*QECK
PPP3CC SQATGFPSLITIFSAPNYLDVYNNK*AAVLK
UCHLS QLIPLVEKAK*
USP 1 5 GPSTPNVK*NSNYCLPSYTAYK
HUNK K*PEPHQPGPGSTGIPHK*EDPLMLDM#VR
CPSF6 KTTQSGQMSGEGK*AGPPGGSSR
HNRNPR IK*ALLER
SYNCRIP ER
MORC3 STNQQTATDVSTSSNIEESVNHM#DGESLK*LR
PABPCI VVCDENGSK*GYGFVHFETQEAAER
ABCEl STALK*ILAGK
C70rf42 QSNPEFCPEK*VALAEA
MLCl K*GSMSDSANILDEVPFPAR
SLC35F2 TAEPAESSVPPVTSIGIDNLGLK*LEENLQETHSAVL
TMEM57 KHNLGINNNNILQPVDSKIQEIEYM#ENHINSK*
POLRZL CFTCGKIVGNK*WEAYLGLLQAEYTEGDALDALGLKR
RSFl AQIDPVLLK*NSSQQDNSSR
SP 1 40 MK*ESPGSQQCCQESEVLER
9468 TBL1XR1 DK*LAQQQAAAAAAAAAAASQQGSAK
10524 RPL30 KSEIEYYAM#LAK*TGVHHYSGNNIELGTACGK*YYR
11010 RPS2 AEDK*EWMPVTK
1101 LOC645018 AEDK*EWMPVTK
11435 1 QFM#IFTQSSEK*TAVSCLSQNDWK
11510 MDM2 ENWLPEDKGKDKGEISEK*
11580 MIB1 SSEDATDDISSGNIPVLQK*DKDNTNVNADVQK
11581 MIB1 SSEDATDDISSGNIPVLQKDK*DNTNVNADVQK
11830 UBE2O STDSQCGTVIDVNIDCAVK*LIGTNCIIYPVNSK
11969 ANKRD13A LTLDLM#KPK*
12110 C130rf40 KPDLRIIEQEEK*
12127 C190rf43 VLTSK*GDAWAK
12129 C190rf43 VLTSKGDAWAK*
12171 CAPN8 LAGKDSEITANALK*
12259 COPS8 K*PVAGALDVSFNKFIPLSEPAPVPPIPNEQQLAR
12322 DDIT4 K*LYSSEQLLIEEC
12432 FAM114A1 SVLTGGLDALEFIGK*
12564 HSPBP1 AMQQQVQK*LK
12929 PLIN2 GAVTGSVEK*TK
12930 PLIN2 GAVTGSVEKTK*
13264 STRBP VM#K*FPTYPVPHYSFF
13561 WDR6 MVK*VDPETR
13849 VAMP8 NLQSEVEGVK*NIMTQNVER
2097 HIST1H1A K*ALAAAGYDVEK,\JNSR
2097 HIST1H1C K*ALAAAGYDVEK,\JNSR
2097 HIST1H1D K*ALAAAGYDVEK,\JNSR
2097 HIST1H1E K*ALAAAGYDVEK,\JNSR
2097 HIST1H1T K*ALAAAGYDVEK,\JNSR
3242 MY018A INSLQDMVTK*YQKR
4677 UAP1 LTLSK*AGQEHLLR
8262 SLC3A2 IK*VAEDEAEAAAAAK
6.18 Efficacy of lenalidornide in activated B-cell like subtype DLBCL
is dependent upon expression of IRF4 and CRBN
Cellproliferation assay
Cell proliferation was assessed using the 3H-thymidine incorporation assay. Briefly,
logarithmically growing DLBCL cells were cultured in 96-well culture plates in complete media
with the indicated concentration of lenalidomide or DMSO control. Following incubation at
37°C for 5 days, 1 uCi midine (GE care Biosciences, Piscataway, NJ) was added to
each well for the final 5 hours of incubation. Cells were then harvested onto UniFilter GF/C filter
plates (PerkinElmer, Waltham, MA) using a cell ter (Tomtec, Hamden, CT) and the plates
were allowed to dry overnight. The 3H-thymidine incorporation of each well was then measured
using a TopCount NXT Microplate Scintillation and Luminescence Counter (Packard
BioScience, Meriden, CT). The percent inhibition of cell proliferation was calculated and
normalized to DMSO control.
Protein sion is
Cells were treated with test compounds or 0.1% DMSO for indicated times. ing
incubation, cells were collected, pelleted with centrifugation, and immediately lysed in 0.1 ml
lysis buffer containing 10 mM Tris-HCl pH 8.0, 10 mM EDTA, 150 mM NaCl, 1% NP-40, 0.5%
SDS, 1 mM DTT, 1 mM N33VO4, plus Complete protease inhibitor cocktail (Roche Applied
Science, Indianapolis, IN), then processed with a QiashredderTM (Qiagen, Valencia, CA) for 1
minute and frozen on dry ice. Samples were diluted with 6 X SDS sample buffer and then boiled
for 5 min. Approximately 30 ul of this mixture was loaded per lane on a Criterion Precast 4—12%
Tris-HCl gel (Bio-Rad, Hercules, CA), electrophoresed, and erred to nitrocellulose
membranes ad, Hercules, CA). The membranes were blocked for 1 hour at room
ature using blocking buffer (LI-COR Biosciences, Lincoln, Nebraska), then incubated
overnight at 4°C with antibodies against either BCL-lO, IRF4, CRBN or B-actin. Membranes
were washed and ted with IRDye ary Antibodies (1 :30,000) for 1 hour at room
temperature. A standard protocol was then followed for signal detection, using the Odyssey®
Infrared Imaging System and software R Biosciences, Lincoln, NE).
NF-nB activity assays
Logarithmically growing DLBCL cells were treated with test agents as indicated. Nuclear
extracts were ed using a Nuclear t Kit (Active Motif, Carlsbad, CA) and protein
concentration was determined by the bicinchoninic acid assay (Thermo Scientific, Rockford, IL).
Detection ofNF-KB activity was performed using a sensitive oligo-based colorimetric enzyme-
linked immunosorbent assay (ELISA) method, according to the instructions of the manufacturer
(Active Motif). Briefly, nuclear extracts of DLBCL cells were hybridized to 96-well plates
coated with wild-type DNA oligonucleotides containing a single copy of the NF-KB sus
binding sequence. Bound NF-KB protein was then detected with antibodies c for p50, p65
(Rel A) or p70 subunits. A ary antibody conjugated to horseradish peroxidase was added
and plates were then read by spectrophotometry at 450 nm with a nce wavelength of 655
nm. NF-KB activity was calculated based on OD450/655 nm.
For the NF-KB n luciferase reporter gene assay, cells were transfected with the
2 /NF-KB-RE/Hygro] plasmid (Promega, Madison, WI) using Nucleofector kit V
and program 013 according to the manufacturer’s ol (Amaxa Biosystems, Gaithersburg,
MD). After 24 hours of transfection, cells were treated with test agents for 2 days and lysates
were prepared using the Dual-Glo® Luciferase Assay System (Promega). Luciferase activities of
each sample were measured using a TopCount NXT Microplate Scintillation and Luminescence
Counter (Packard BioScience).
Real-time quantitative reverse transcriptase-PCR analysis
After 48 hours of cell treatment, total RNA was purified with RNeasy® Mini Kits using
QiaCubeTM system (Qiagen Inc., Valencia, CA). Real-time quantitative RT-PCR with 25—100 ng
of total RNA was performed using the reverse transcription kit and Taqman® PCR probes
specific for the genes of interest according to standard methods (Applied Biosystems Inc.). The
quantity of product was normalized to glyceraldehydephosphate ogenase as the
endogenous housekeeping gene. Fold increase of gene expression was calculated using
comparative Ct method (Z'AACt).
Electroporation for overexpression and knockdown ofIRF4
To knockdown IRF4, cells were ected with er® Select siRNA (small
interfering RNA, Applied Biosystems) ed against [RF4, CRBN, or Silencer® Select
Negative Control siRNAs at a final concentration of 0.2—1 uM using Nucleofector® Kit V for
2012/035429
transfection. For IRF4 pression, cells were transfected with IRF4- or green fluorescent
protein (GFP)— cytomegalovirus (CMV) expression plasmids (OriGene Technologies, Rockville,
MD) for 24 h using the Cell Line Nucleofector kit V as above-mentioned. After 24 hours of
transfection, cells were treated with lenalidomide for 2 days before luciferase assay, RT-PCR
gene expression analysis and Western blot.
Human tumor xenograft model
Female CB17 severe combined immunodeficiency (SCID) mice (6-12 weeks old) were
obtained from the s River Laboratory (Wilmington, MA) and maintained in microisolator
cages under sterile conditions. A total of 10 X 106 OCI-Ly10 DLBCL cells in 100% Matrigel
(Becton Dickinson, San Jose, CA) were injected subcutaneously into the right flank of mice.
Mice were monitored 2 or 3 times a week for the appearance of tumors. Once the tumors reached
an average size of 100 - 150 mg, 10 mice in each group were treated with either vehicle (0.5%
carboxymethyl ose: 0.25% Tween 80 in deionized H20) or indicated doses of lenalidomide
(qd x 28, p.o.) or the positive control vincristine (q4d x 4, iv). Mice were monitored daily for
health status as well as tumor growth. Tumors of all mice were measured with a l caliper
and volumes calculated with the following formula: tumor volume (m3) = length (mm) X width
(mm)2. Mice were killed when tumor size exceeded 1000 mm3.
Statistical analysis
es for multiple group comparisons were performed with one-way analysis of
variance, followed by Dunnett’s post-test, and correlation analyses were carried out using the
two-tailed P-value n test using GraphPad Prism® version 5.01 (San Diego, CA). A value
of P < .05 was ered significant in all analyses.
Results
6.18.1 ABC-DLBCL cells are more sensitive to lenalidomide than
non-ABC-DLBCL cells
In order to define the place of lenalidomide for DLBCL therapy in specific patient
populations and to understand the molecular mechanisms of y, a panel of DLBCL cell
lines was collected in this study. The DLBCL subtypes of the cell lines were confirmed based on
literature ation (Lenz G, et al., Proc Natl Acad Sci U S A 2008; 105: 13520-5) and
molecular analysis, including intracellular NF-KB activity or IRF4 expression, as well as gene
expression ing of key signature genes of activated B cells. See Figures 24A-24C. Cell
WO 49299
proliferation of DLBCL cell lines was found to be inhibited to various degrees by treatment with
lenalidomide at a concentration range of 0.01 - 100 uM. Lenalidomide had minimal effects on
proliferation of PBML and GCB-DLBCL cells, but significantly inhibited proliferation ofABC-
DLBCL cell lines, except for OCI-Ly3. See Figure 24. Lenalidomide treatment also induced
apoptosis of sensitive cell lines such as OCI-Ly10. See Figure 26.
6.18.2 Lenalidomide reduces IRF4 sion in ABC-DLBCL cells
To understand the molecular mechanism of lenalidomide on ABC-DLBCL cells, the
s of lenalidomide on IRF4 expression in these cells were investigated. Lenalidomide
treatment for 1-3 days was found to significantly downregulate IRF4 protein levels in sensitive
cell lines such as U2932 and OCI-Ly10, but not the insensitive line OCI-Ly3 cells. See Figures
27A-C. Lenalidomide-induced decrease of IRF4 expression occurred as early as 1 day of drug
ent, with similar cs to that of the tors (zVRPR-fmk and LY-333,53 l ,
respectively) of MALTl and PKCB, two key enzymes involved in NF-KB activation upon BCR
engagement in B cells. In 3 cells, r lenalidomide nor the PKCB inhibitor had any
appreciable effect on IRF4 levels during 1-3 day treatments. r, the MALTl inhibitor
ssed IRF4 expression in OCI-Ly3 cells, with complete inhibition observed after 2-3 days
of treatment. Taken together, these data suggest that lenalidomide-mediated inhibition of IRF4
expression may be an important mechanism and s to be related to cell sensitivity to the
drug.
6.18.3 Lenalidomide reduces CARDl 1-BCLMALT1 complex
activity of ABC-DLBCL cells
Our DNA sequencing data confirmed previous reports (Lenz, G., et al., Science 2008,
319: 1676-9) that the lenalidomide-insensitive ABC-DLBCL line OCI-Ly3 has a unique point
mutation in CARD] 1 within the exons ng the coiled-coil domain, while lenalidomide-
sensitive ABC-DLBCL lines OCI-Ly10, U2932, TMD8, and Riva do not. See Figure 28. This
mutation has been reported to cause constitutive formation and activation of CARDl l-BCL
MALTl (CBM) complex of BCR signaling pathway, leading to NF-KB overactivation in
lymphoma cells. See Lenz, G., et al., Science 2008, 319: 1676-9; Thome, M. et al., Cold Spring
Harb Perspect Biol. 2010; 2: a003004. To igate the potential involvement of CBM
complex in lenalidomide-induced IRF4 inhibition in these cells, the effect of lenalidomide on the
complex activity was examined by measuring MALTl paracaspase enzymatic activity. MALTl
is activated upon association with BCL-lO and CARDll to form active CBM complex and then
s its binding partners, such as BCL-lO.. See Figures 29A-C.
Similar to the effect of the specific MALTl inhibitor and PKCB inhibitor, lenalidomide
inhibited MALTl-induced BCL-lO cleavage in a concentration-dependent manner in the
sensitive ABC-DLBCL cell lines OCI-Lle and U2932. Time-kinetic studies revealed that
while MALTl- and PKCB-inhibitors affected BCL-lO cleavage within 1 day of treatment,
significant inhibition of BCL-lO cleavage by lenalidomide occurred after 2 days of treatment.
See Figures 29A and 29B. Unlike the MALTl inhibitor, neither the PKCB tor nor
lenalidomide had any effect on BCL-lO cleavage in 3 cells, presumably due to CARDll
mutation which causes ctivation of CBM complex. See Figure 29C. These data suggest
that lenalidomide, similar to the PKCB tor, can significantly block CBM complex
formation/activation or other upstream events in sensitive ABC-DLBCL cells.
6.18.4 domide reduces NF-KB activity of ABC-DLBCL cells but
not non-ABC subtype cells
The effect of lenalidomide on NF-KB ty in various DLBCL cells was examined by
measuring the level ofNF-KB subunit proteins binding to consensus ces and the NF-KB-
driven luciferase ty. As expected, NF-KB in ABC-DLBCL cells demonstrated increased
NF-KB DNA binding ed to non-ABC-DLBCL. See Figure 24B. An NF-KB-driven
luciferase assay demonstrated that lenalidomide inhibited transcriptional activity ofNF-KB by
32-56% in the lenalidomide-sensitive ABC-DLBCL cell lines OCI-Lle and U2932 after 2 day
drug treatment. See Figure 30A. Lenalidomide also partially inhibited DNA g by Rel A/
p65, p50 and c-rel/p70 NF-KB subunits in a concentration-dependent manner in several ABC-
DLBCL cell lines, although the effect was not as potent as the control IKKu/B inhibitor CC-
4l550l. See Figures 30B and 30C. In contrast, lenalidomide had no effect on NF-KB DNA
binding in GCB-DLBCL lines nor in normal peripheral blood clear cells. The
lenalidomide-insensitive ABC-DLBCL OCI-Ly3 line containing the CARDll mutation showed
signif1cantNF-KB inhibition only by the IKKu/B inhibitor, and not by lenalidomide. See Figures
30B and 30C. These data t that lenalidomide inhibits NF-KB signaling at CBM complex
or upstream events in sensitive ABC-DLBCL cells.
6.18.5 Alteration of IRF4 expression in ive ABC-DLBCL cells
confers resistance to lenalidomide
The dependency role of IRF4 expression in -KB signal transduction and the
sequent effects of lenalidomide treatment upon IRF4 were investigated. domide-sensitive
BCL cells were transfected with IRF4-specific siRNA or MV-based expression
plasmid to modulate IRF4 expression. When U2932 or OCI-Lle cells were transfected with
IRF4 siRNA to knock down the expression of IRF4, NF-KB transcriptional ty was
diminished by 36-53%. See Figure 31A. Thus IRF4 siRNA mimicked the effects of
lenalidomide on NF-KB in these cells. The addition of lenalidomide to the IRF4 siRNA-
transfected cells led to even fithher downregulation ofNF-KB transcriptional activity.
In contrast to IRF4 siRNA transfection, over-expressing IRF4 in these cells for 24 h
significantly increased NF-KB activity by 3.6-7.9 fold. See Figure 31B. Furthermore, IRF4
overexpression decreased protein expression levels of the CBM-component BCL-lO. See Figure
3 1C. In addition, IRF4 overexpression antagonized the effect of lenalidomide and the PKCB
inhibitor but not the IKK inhibitor on NF-KB -driven luciferase expression in both U2932 and
OCI-Lle cells. See Figure 31D. Therefore, the positive feedback effect of IRF4 on the BCR-
NF-KB pathway appeared to be at a point somewhere between PKCB and IKK.
6.18.6 Cereblon is required for lenalidomide effect on ABC-DLBCL
cells
Cereblon has been shown to be a primary mediator of the teratogenicity of thalidomide.
Due to its critical role in the anti-myeloma and modulatory activities of lenalidomide
and pomalidomide, the role of cereblon in domide sensitivity of DLBCL was igated.
In ABC-DLBCL cells, knockdown of CRBN with siRNA conferred resistance to lenalidomide as
demonstrated by the abrogation of the inhibitory effects of lenalidomide on IRF4 expression,
BCL-lO cleavage, NF-KB activity and eration of these cells, while the activity of inhibitors
to PKCB and IKK remained unaffected. See Figures D. These data indicate that
antitumor effects of lenalidomide on ABC-DLBCL cells require the presence of cereblon.
6.18.7 Lenalidomide down-regulates IRF4/NF-KB signaling in
OCI—Ly10 mouse xenograft model
To confirm the relevance of lenalidomide-mediated inhibition ofNF-KB/IRF4 signaling
in vivo in ABC-DLBCL, a subcutaneous OCI-Lle aft model was established.
Lenalidomide at 3-30 mg/kg (po, qu28) significantly decreased tumor size in this model
(p<0.01). See Figure 33A. No pronounced toxicity of lenalidomide was observed based upon
mouse weight throughout study. Compared with vehicle control group, lenalidomide ent
for 7 days reduced IRF4 expression and BCL-lO cleavage by 15-35% (p<0.05). See Figure 33B.
These data demonstrate that lenalidomide can reduce IRF4 expression in vivo and delays tumor
growth in an ABC-DLBCL model, supporting the potential value of lenalidomide as a
therapeutic in the treatment ofABC-DLBCL in clinical studies.
6.18.8 IRF4 and CRBN baseline mRNA levels and “ABC scores” of
DLBCL cells ate with sensitivity to lenalidomide
As multiple studies have demonstrated r lenalidomide sensitivity ofABC-DLBCL
cells versus non-ABC-subytpes, potential biomarkers predictive for a therapeutic response to
lenalidomide were studied. Pooled in vitro data from eleven DLBCL cell lines of various
subtypes showed that lenalidomide sensitivity of DLBCL subtypes highly correlated to the
baseline level of IRF4 and CRBN mRNA expression. onally, the overall “ABC score,”
calculated based on baseline levels of signature genes DLBCL cells proposed by Staudt,
et al. (Ann. Rev. Med, 2002, 53: 303-18), correlated to lenalidomide activity and further
s the unique sensitivity of this subtype. See Figures 34A and 25. Lenalidomide-sensitive
ABC-DLBCL cell lines tended to express higher CRBN and IRF4 n levels than GCB-
DLBCL cell lines. See Figure 34B. Notably, the lenalidomide-resistant OCI-Ly3 BCL
cell line was devoid of CRBN protein expression. These data support the preferential efficacy of
lenalidomide in ABC-DLBCL seen in clinical studies, and suggest that the “ABC score,” or the
expression of IRF4 or CRBN , may serve as potential biomarkers for the prediction of
lenalidomide efficacy.
6.19 Polyclonal CRBN70 antibody
Rabbit polyclonal antibody CRBN70 was generated by inoculating s with the
CRBN peptide sequence TLHDDD (SEQ ID: 1), wherein a C-terminal cysteine
TLHDDDQ (underlined) is fiarther used to couple the peptide to Keyhole Limpet
Hemocyanin (KLH).
VV()2012/149299
The e depicted in SEQ ID NO:1 used to make the antibody ponds to amino
acids 65-76 d) of CRBN m 1 (NP_057386) (SEQ ID NO:12):
magegdqqda ahnmgnhlpl 1p§eseeede mevedquke akkpniinfd tsttshtyl
61 gadmeefhgr tlhdddscqv ipv1pqvmmi Wipgqt1p1q 1fhpqevsmv rnLiqkdrtf
121 avlaysnvqe reaquttae iyayreeqdf vkai vLel rtqsdgiqqa
181 ecv; pstmsavqle slnkcqifps kpvsredqcs ykwququr kfhcanLtsw
241 prwlyslyda etlmdrikkq Lrewdenlkd dslpsnpidf syrvaachi ddvlriqllk
301 igsaiqurc eldimnkcts Lccchqete ittkneifsl slcgpmaayv nphgyvhetl
361 tvykacn'n' igrpstehsw tvaq ckicashigw kftatkkdms qufngtrs
421 allptipdte deispdkvil c1
It is noted that isoform 2 of CRBN (GenBank Acession No. NP_001166953; SEQ ID
NO: 13) uses an ate in frame splice site that results in the elimination of the alanine
(underlined), but has no other changes:
1 magegdqqda ahnmgnh'pl 'peseeedem evedqukea kkpniinfdt sttshtylg
61 admeefhgrt 1hdddscqvi pv1pqvmmi1 ipgqt1p1q1 fhpqevsmvr nLiqkdrtfa
121 Vlaysnvqer eaquttaei yayreeqdfg ieivkvkaig rqrfkvLelr tqsdgiqqak
181 vqilpecv;p stmsavq'es 'nkcqifpsk pvsredqcsy rk fhcanLtswp
241 rwlyslydae kkq; rewdenlkdd slpsnpidfs yrvaachid dvlriqllki
301 gsaiqurce 1dimnkcts; ccchqetei ttkneifsls lcgpmaayvn phgyvhetlt
361 vykacn'n'i hswf pgyawtvaqc kicashigwk ftatkkdmsp qkfngtrsa
421 llptipdted eispdkvilc 1
The polyclonal CRBN70 antibody was purified. Purified antibody was then titered by
indirect ELISA against the peptide or protein bound to a solid-phase to measure the reactiVity of
the antibodies after elution and the amount of antibody ing in serum (the flow-through).
Sample Volume Conc. Total Titer Flow-
(mL) (mg/mL) (mg) (n9) ""0"?!"
CRBN70 _————
The eluent “titer” indicates the minimum concentration at which the CRBN70 dy
can effectively detect the CRBN antigen. The “flow-through” titer represents the reactiVity of
the antibodies remaining in the serum after it has been passed through the column.
6.20 Sequences of VH and VL of anti-CRBN antibodies
Rabbits were primed with amino acid sequence 65-76 (SEQ ID NO: 1) of human CRBN
(SEQ ID NO: 12), and the spleen was removed for IgG subtyping and monoclonal antibody
creation.
The IgG heavy and light chains from two CGN—6 hybridoma clones were sequenced by
Epitomics. The two clones were CGN—6-l-ll and CGN—65.
Briefmethods description ofRabMAb IgG molecular cloning:
Messenger RNA (mRNA) from hybridoma cells was isolated using APTURE
Kit (Qiagen: Catalog #72232) ing the manufacturer’s suggested protocol, and then reverse
transcribed into cDNA using dT primer. The variable region of heavy chain (VH) was PCR
amplified using proprietary primers OYZ64-2 and OYth3. The entire light chain (LC) was
PCR amplified using proprietary primers OYZ62 and OYZ7l. The PCR products were resolved
on 1% argrose gel ed by purification using Qiagen gel purification kit (Qiagen: Catalog
#28704), and the d DNA fragments were subjected to sequencing.
CGNl-l l- Heafl chain nucleotide seguence (SEQ ID NO:4):
ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCACTGTCAGTCAGTGGAGGAGTCCGG
GGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGTACAGTCTCTGGATTCTCCCTCAGTTACTATGGAG
TGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTAGAATACATCGGATACATTTATAGTGATAGTGATAAGACATAC
TACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATTTGAAAATCACCAGTCCGAC
AATCGAGGACACGGCCACCTATTTCTGTGCCAGAGGTACTCCGCTTGCTAG?TATAGCATCTGGGGCCCAGGCACCC
TGGTCACCGTCTCCTTAGGGCAACCTAAGGCTCCATCAGTCTTCCCACTGGCCCCCTGCTGCGGGGACACACCCAGC
GTGACCCTGGGCTGCCTGGTCAAAGGGTACCTCCCGGAGCCAGTGACCGTGACCTGGAACTCGGGCACCCT
CACCAATGGGGTACGCACCTTCCCGTCCGTCCGGCAGTCCTCAGGCCTCTACTCGCTGAGCAGCGTGGTGAGCGTGA
CCTCAAGCAGCCAGCCCGTCACCTGCAACGTGGCCCACCCAGCCACCAACACCAAAGTGGACAAGACCGTTGCGCCC
TCGACATGCAGCAAGCCCACGTGCCCACCCCCTGAACTCCTGGGGGGACCGTCTGTCTTCATCTTCCCCCCAAAACC
CAAGGACACCCTCATGATCTCACGCACCCCCGAGGTCACATGCGTGGTGGTGGACGTGAGCCAGGATGACCCCGAGG
TGCAGTTCACATGGTACATAAACAACGAGCAGGTGCGCACCGCCCGGCCGCCGCTACGGGAGCAGCAGTTCAACAGC
ACGATCCGCGTGGTCAGCACCCTCCCCATCGCGCACCAGGACTGGCTGAGGGGCAAGGAGTTCAAGTGCAAAGTCCA
CAACAAGGCACTCCCGGCCCCCATCGAGAAAACCATCTCCAAAGCCAGAGGGCAGCCCCTGGAGCCGAAGGTCTACA
CCATGGGCCCTCCCCGGGAGGAGCTGAGCAGCAGGTCGGTCAGCCTGACCTGCATGATCAACGGCTTCTACCCTTCC
GACATCTCGGTGGAGTGGGAGAAGAACGGGAAGGCAGAGGACAACTACAAGACCACGCCGGCCGTGCTGGACAGCGA
CGGCTCCTACTTCCTCTACAGCAAGCTCTCAGTGCCCACGAGTGAGTGGCAGCGGGGCGACGTCTTCACCTGCTCCG
TGATGCACGAGGCCTTGCACAACCACTACACGCAGAAGTCCATCTCCCGCTCTCCGGGTAAATGA
CGNl-l l- Heavy chain p_rotein seguence (SEQ ID \IO:5):
mZL—‘FUI—ZIKIWK?TG.RW..LVAV.KGVHCQSVfiflSGGRLVTPGTPLTJTCTVSGFSJSYYGVSWVRQAPG4036) C).?YIGYIYSDSDKTYYATWA<GRFTISKTSTTVDL<ITS?TIEDTATYFCARGTPLASIWGPGTIVTVS.GQPKA?SVF?LAPCCGDTPSSTVTLGCIVKGYIP?PVTVTWNSGT4VRTF?SVRQSSGJYSLSSVVSVTSSSQPVTCNVAiPATVTKVD{TVAPSTCSKPTC?N'U_l.iLLiG UPO. FIF?P{PKDTLMISR?PEVTCVVVDVSQDDPEVQFTWYINNEQVRTARP?QFVSTIRVVSTJPIAiQDW.RGK?F<C<VHNKAIPAPI?KTISKARGQPLEPKVYT U
' _RnnISSRSVSLTCMIVGFY?SDISVanKNGKAnDNY{DTPAVLDSDGSYFLYSKJ
V?TSEWQRGDVFTCSVMHEALHVHYTQKSISRSPGK-
CGNl-l l- Light chain nucleotide seguence (SEQ ID NO:6):
40 ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCCAGGTGCT
GACCCAGACTCCAGCCTCGGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTCAGAGTGTTT
ATAAGAATAACTATTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATTTACGAAGCGTCCAAA
CTGGCATCTGGGGTCCCCCCGCGGTTCAAAGGCAGTGGATTTGGGACACAGTTCACTTTCACCATTAGCGACCTGGA
GTGTGACGATGCTGCCTTTTACTACTGTGCAGGCGGTTATTATGGTAATATTTTTTTTTTCGGCGGAGGGACCGAGG
TGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACA
GTCACCATCGTGC1G?1GTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAAC
AACTGGCAT1CGAGAACAGTAAAACACCGCAGAATTCTGCAGAC1TGTACCTACAACCTCAGCAGCACT1CTGACACC1GA
CCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGT1GACCCAGGGCACGACCTCAGTCGT1CCAGAGCC1TC
AATAGGGGTGACTGT1TAG
CGN1 Light chain protein ce (SEQ ID NO:7):
MDT RAPTQL.GLL .LWLPGATFAQVLTQTPASVSAAVGGTVTINCQASQSVY {NNYLSWF
QQK ?GQP?K.TIY TASKLASGVPPREKGSGEGTQETbTISDLLCDDAAEYYCAGGYYGNI
FFFGGGTEVVVKG DPVAPTVLIFPPAADQVATGTVTIVCVAN{YFPDVTVTWEVDGTTQT
TGI PQNSA DCTYNLSSTLTLTSTQYNSHK LYTCKVTQGTTSVVQSFNRGDC-
CGN4 Heafl chain nucleotide seguence (SEQ ID NO:8):
ATGGAGACT1GGGCTGCGCT1GGCTTCTCCTGGC1CGCTGTGCTCAAAGGTGTCCAGTGTCAGC1CGGTGGAGGAGC1CCGG
GGGTCGCCT1GGTCACGCCT1GGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAGGTAC1GGAG
TGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCT1GGAACACATCGGATACATTTATAG.TGAE1CC?1GGTATGACAC1TC
TACGCGACCF1GGGCGAAAGGCCGAT TCACCAC1CC1CCAAAACCTCGTCGACCACGGTGGATr .1GAAAAC1GACCAGC1CC
GACAA.1CGAGGACACGGCCACCT1Ar 1Tcr1GTGCCAGAGGTACC1CCGCTTGCTAGTTATAGCACCC1GGGGCCCAGGCA
CCCC1GGTCACCATCC1CCTTAGGGCAACCTAAGGCTCCATCAG:1CTTCCCACTGGCCCCCTGCTGCGGGGACACACCC
AGCT1CCACGGTGACCCTGGGCT1GCCr1GGr‘CAAAGGGTACCC1CCCGGAGCCAGTGACCGTGACCTGGAACTCGGGCAC
CCTCACCAATGGGGr1ACGCACCT1TCCCGr1CCGTCCGGCAGTCCC1CAGGCCTCTACTCGCTGAGCAGCGTGGTGAGCG
TGACCTCAAGCAGCCAGCCCGF1CACCTGCAACGTGGCCCACCCAGCCACCAACACCAAAGT1GGACAAGACCGT1TGCG
CCCTCGACATGCAGCAAGCCCACGTGCCCACCCCCTGAACTCCT1GGGGGGACCGTCTGTCr1TCAC1CTTCCCCCCAAA
ACCCAAGGACACCCT1CAC1GATCC1CACGCACCCCCGAGGTCACAC1GCGTGGTGGTGGACGTGAGCCAGGAF1GACCCCG
AGGTGCAGTTCACAC1GGC1ACATAAACAACGAGCAGGTGCGCACCGCCCGGCCGCCGCT1ACGGGAGCAGCAGT TCAAC
AGCACGAC1CCGCGT1GGTCAGCACCCTCCCCATCGCGCACCAGGACTGGCTGAGGGGCAAGGAGTT1CAAGC1GCAAAGT
CAAGGCACT1CCCGGCCCCCATCGAGAAAACCAC1CTCCAAAGCCAGAGGGCAGCCCCTGGAGCCGAAGGTCT
ACACCAC1GGGCCCT1CCCCGGGAGGAGCTGAGCAGCAGGT1CGGTCAGCCTGACCTGCATGATCAACGGCT TCTACCCT
AC1CTCGGr1GGAGT1GGGAGAAGAACGGGAAGGCAGAGGACAACC1ACAAGACCACGCCGGCCGT1GCTGGACAG
CGACGGCr1CCTACC 1ccr1CTACAGCAAGCT1CTCAGTGCCCACGAGT1GAGTGGCAGCGGGGCGACGT1CC TCACCTGCT
CCGTGAC1GCACGAGGCCr TGCACAACCACC1ACACGCAGAAGTCCATCTCCCGCTCTCCGGGTAAATGA
CGN4 Heafl chain protein seguence 1450 amino acids: (SEQ ID NO: 9):
TTGIRWL..VAVT.KGVQCQSV_1 *SGGRTIVTPGC1PLC1L1CTVSGFSLSRYGVSWVRQAPG
{GLL1IGYIYSDPGMTFYATWA{GRFTISKTSSC1TVDL {MTS ?"1I EDTATYFCARGTPLA
SYS TWGPGTLVTISLGQPKA ?SVFPLAPCCGDTPSSTVTLGC.VKGYTIPTPVTVTWNSGT
LTNGVRTF ?SVRQSSGLYSLSSVVSVC1SSSQPVC1CNVA1PATNC1KVDKTVAPSTCSKPTC
?PP_*J .LGG?SVFIFPP<PKDTL ISRC EVE1CVVVDVSQDDP.LVQFTWYINNLQVRTARP
?LR LQQFWSTIRVVST LPIA DWLRGK? {VHNKAIPAPITKTISKARGQPLLPKVY_1'
3RLLISSRSVSLTCMIWGFYPSDISV. LDNY<C1TPAVLDSDGSYFLYSK
ISV ?TS?WQRGDVFTCSVMHL .HNHYTQKSISRSPGK-
CGN4 Light chain nucleotide seguence (SEQ ID NO: 10):
ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCTCAAGTGCT
GACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGTCCAGTGAGAATATTT
ATAAGAACAACTACTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATCAGGCATCCACT
CTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACGATTCAGTCTCACCATCAGCGACCTGGA
GTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTATAGTGGTAATATTTTTACTTTCGGCGGAGGGACCGAGG
TGGTGGTCAAAGGTGATCCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTGGCAACTGGAACA
GTCACCATCGTGTGTGTGGCGAATAAATACTTTCCCGATGTCACCGTCACCTGGGAGGTGGATGGCACCACCCAAAC
AACTGGCATCGAGAACAGTAAAACACCGCAGAATTCTGCAGATTGTACCTACAACCTCAGCAGCACTCTGACACTGA
CCAGCACACAGTACAACAGCCACAAAGAGTACACCTGCAAGGTGACCCAGGGCACGACCTCAGTCGTCCAGAGCTTC
AATAGGGGTGACTGTTAG
CGN4 Light chain n seguence (SEQ ID \10: l l):
MDTRAPTQLJGLLLLWLPGATFAQVLTQTPASVSAAVGGTVTINCQSSENIY{NNYLSWF
QQK?GQP?K4LIYQASTLASGVPSRFKGSGSGTRFSLTISDLECDDAATYYCAGGYSGNI
FTFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVAN{YFPDVTVTWEVDGTTQT
TGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC-
Amino acid sequence alignments of the heavy and light chains of the CGN6-l-ll and
CGN 65 antibodies are provided in Figures 35 (heavy chains) and 36 (light ).
6.21 Immunoblot and immunofluorescnce with monoclonal anti-CRBN
antibody, CGN4-5
Rabbit monoclonal antibody CGN4-5 specifically recognizes the fiJll-length 51 kDa
human CRBN protein on ring immunoblots.
Confocal microscopic Immunofluorescence:
CGN4-5 was diluted 1:1000. Exemplary sell staining of DFl5 and DFl5R cells is
shown in Figure 37. In particular, Figures 37A and 37B depict confocal immunofluorescent
analysis of DFl5 (left panel) and DFl5R cells (right panel) using I ug/ml 4-5 antibody
(green) (A) or CGN4-5 antibody/ CRBN blocking e mix (1:5 excess ratio) (B).
Nuclear staining was performed with Dapi .
Immunoblot
CGN4-5 was diluted 1: 10,000 on in 0.1% Tween PBS buffer. An exemplary
immunoblot with myeloma cells containing endogenous CRBN (DFl5), DFl5R with no CRBN
and HEK293 cells expressing recombinant flag-tagged CRBN is shown in Figure 38. Peptide
neutralization was performed by combining antibody with a old (by weight) excess of
blocking peptide in 500 ul PBS and incubating with constant rotation at room temperature for 2
hours.
WO 49299 2012/035429
6.22 omide, lenalidomide and pomalidomide bind to CRBN via
the glutarimide moiety
The binding of pthalimide and glutarimide to CRBN was investigated in order to
elucidate the mechanism of CRBN binding of thalidomide, lenalidomide, pomalidomide and
structurally similar compounds. Glutarimide bound to CRBN while pthalimide did not. Thus,
these results t the hypothesis that thalidomide, lenalidomide and pomalidomide bind to
CRBN via the glutarimide moiety. See Figure 39A.
6.23 CRBN binding of methyl-pomalidomide is enantioselective
The binding of S-methyl-pomalidomide and R—methyl-pomalidomide was investigated in
order to determine whether CRBN binding is enantioselective. S-methyl-pomalidomide had
greater affinity for CRBN than R—methyl-pomalidomide limide. See Figure 39B.
0 O O O
NH NH
N o N o
0 0
NH2 NH2
S—methyl-pomalidomide yl-pomalidomide
The es set forth above are provided to give those of ry skill in the art with a
complete disclosure and description of how to make and use the claimed embodiments, and are
not intended to limit the scope of what is disclosed herein. Modifications that are obvious to
persons of skill in the art are intended to be within the scope of the following claims. All
publications, patents, and patent applications cited in this specification are incorporated herein by
reference as if each such publication, patent or patent application were specifically and
individually indicated to be incorporated herein by reference.
Claims (18)
1. A method of identifying a drug sensitive cancer patient in a group of cancer patients comprising: determining the sion level of cereblon (CRBN) in a biological sample of a cancer, which has been ed from a cancer patient; predicting clinical response, monitoring clinical response, or monitoring patient compliance to dosing by a drug, based on the sion level of CRBN, wherein the cancer patients are diffuse large B-cell lymphoma patients; and n the drug is thalidomide, lenalidomide, pomalidomide or 3-(5-aminomethyl oxo-4H-quinazolinyl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
2. A method of predicting the likelihood of a patient having diffuse large B-cell lymphoma being responsive to treatment with a drug, comprising: ining the expression level of cereblon (CRBN) in a biological sample of said diffuse large B-cell lymphoma, which has been ed from the t; and predicting clinical response, monitoring clinical response, or monitoring patient compliance to dosing by a drug, based on the expression level of CRBN; wherein the drug is thalidomide, lenalidomide, pomalidomide or 3-(5-aminomethyl oxo-4H-quinazolinyl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
3. The method of claim 1 or 2, wherein the diffuse large B-cell lymphoma is of the activated B-cell–like subtype.
4. The method of claim 1 or 2, wherein a higher expression level of CRBN indicates a higher likelihood of the cancer being responsive to a treatment with the drug.
5. The method of claim 1 or 2, wherein the expression level of CRBN is determined using an anti-CRBN antibody, said dy immunospecifically binds to an epitope of CRBN, said epitope having the amino acid sequence of SEQ ID NO:1.
6. The method of claim 5, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:5 and a light chain having the amino acid sequence of SEQ ID NO:7.
7. The method of claim 5, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:9 and a light chain having the amino acid ce of SEQ ID NO:11.
8. Use of a drug selected from omide, lenalidomide, pomalidomide or 3-(5- aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in the manufacture of a medicament for the treatment of diffuse large B-cell ma in a t in need thereof, wherein said t has a higher expression level of CRBN in said diffuse large B-cell lymphoma.
9. Use of an anti-CRBN antibody in the manufacture of a diagnostic agent for predicting clinical response, monitoring al response, or monitoring t compliance to dosing by a drug in a cancer patient, based on the expression level of CRBN, wherein the cancer patients are diffuse large B-cell lymphoma patients; and wherein the drug is thalidomide, lenalidomide, pomalidomide or 3-(5-aminomethyloxo-4H-quinazolinyl)-piperidine-2,6- dione, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
10. The use of claim 8 or 9, wherein the diffuse large B-cell lymphoma is of the activated B-cell–like subtype.
11. The use of claim 8 or 9, wherein a higher sion level of CRBN indicates a higher likelihood of the cancer being responsive to a treatment with the drug.
12. The use of claim 8 or 9, wherein the expression level of CRBN is determined using an anti-CRBN antibody, said dy immunospecifically binds to an epitope of CRBN, said epitope having the amino acid sequence of SEQ ID NO:1.
13. The use of claim 12, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:5 and a light chain having the amino acid sequence of SEQ ID NO:7.
14. The use of claim 12, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:9 and a light chain having the amino acid sequence of SEQ ID NO:15.
15. A method according to claim 1, substantially as herein described or exemplified.
16. A method according to claim 2, substantially as herein described or ified.
17. A use according to claim 8, substantially as herein described or ified.
18. A use according to claim 9, substantially as herein described or exemplified.
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161481066P | 2011-04-29 | 2011-04-29 | |
US61/481,066 | 2011-04-29 | ||
US201161511986P | 2011-07-26 | 2011-07-26 | |
US61/511,986 | 2011-07-26 | ||
US201161579600P | 2011-12-22 | 2011-12-22 | |
US61/579,600 | 2011-12-22 | ||
PCT/US2012/035429 WO2012149299A2 (en) | 2011-04-29 | 2012-04-27 | Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ617142A NZ617142A (en) | 2015-11-27 |
NZ617142B2 true NZ617142B2 (en) | 2016-03-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10047151B2 (en) | Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor | |
JP6348192B2 (en) | Method for treating cancer using 3- (5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl) -piperidine-2,6-dione | |
EP3160486B1 (en) | Compositions and methods for inducing conformational changes in cereblon other e3 ubiquitin ligases | |
EP3077548B1 (en) | Methods for determining drug efficacy for the treatment of diffuse large b-cell lymphoma, multiple myeloma, and myeloid cancers | |
US11345956B2 (en) | Methods and compositions related to prostate cancer therapeutics | |
US20160008344A1 (en) | Methods for the treatment of non-hodgkin's lymphomas using lenalidomide, and gene and protein biomarkers as a predictor | |
US20140045843A1 (en) | Methods of treating cancer using 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione | |
US20220378773A1 (en) | Methods for treating leukemia and use of a leukemic stem cell signature to predict clinical sensitivity to therapies | |
CN114845716A (en) | Prediction of clinical sensitivity to 2- (4-chlorophenyl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 2-difluoroacetamide using biomarkers | |
US20180238886A1 (en) | Methods for treating hematological cancer and the use of biomarkers as a predictor for responsiveness to treatment compounds | |
NZ617142B2 (en) | Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor | |
US20200118646A1 (en) | Methods of classifying diffuse large b-cell lymphoma | |
WO2017096184A1 (en) | Treatment of diffuse large b-cell lymphoma and of non-hodgkin's lymphome using lenalidomide |