US20230310354A1 - Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer - Google Patents
Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer Download PDFInfo
- Publication number
- US20230310354A1 US20230310354A1 US18/308,961 US202318308961A US2023310354A1 US 20230310354 A1 US20230310354 A1 US 20230310354A1 US 202318308961 A US202318308961 A US 202318308961A US 2023310354 A1 US2023310354 A1 US 2023310354A1
- Authority
- US
- United States
- Prior art keywords
- cancer
- cells
- selective agonist
- cyp26
- rarα
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000556 agonist Substances 0.000 title claims abstract description 155
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 146
- 201000011510 cancer Diseases 0.000 title claims abstract description 89
- 238000011282 treatment Methods 0.000 title claims abstract description 40
- 101150011193 CYP26A1 gene Proteins 0.000 title 1
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 claims abstract description 183
- 108091008726 retinoic acid receptors α Proteins 0.000 claims abstract description 183
- 210000001185 bone marrow Anatomy 0.000 claims abstract description 107
- 102100039282 Cytochrome P450 26A1 Human genes 0.000 claims abstract description 84
- 101000745891 Homo sapiens Cytochrome P450 26A1 Proteins 0.000 claims abstract description 76
- 238000000034 method Methods 0.000 claims abstract description 45
- 210000000130 stem cell Anatomy 0.000 claims abstract description 27
- 230000002829 reductive effect Effects 0.000 claims abstract description 13
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 97
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 89
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 37
- -1 bevacizumab Chemical compound 0.000 claims description 37
- 239000003112 inhibitor Substances 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 20
- 208000009527 Refractory anemia Diseases 0.000 claims description 16
- 206010072684 Refractory cytopenia with unilineage dysplasia Diseases 0.000 claims description 16
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin 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 claims description 14
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 14
- 239000002246 antineoplastic agent Substances 0.000 claims description 14
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 13
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 13
- 230000036210 malignancy Effects 0.000 claims description 12
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 11
- 229960005420 etoposide Drugs 0.000 claims description 11
- 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 claims description 11
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 10
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 10
- 208000007660 Residual Neoplasm Diseases 0.000 claims description 10
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 9
- 208000034578 Multiple myelomas Diseases 0.000 claims description 9
- 208000033501 Refractory anemia with excess blasts Diseases 0.000 claims description 9
- 229960004397 cyclophosphamide Drugs 0.000 claims description 9
- 208000016586 myelodysplastic syndrome with excess blasts Diseases 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 201000005787 hematologic cancer Diseases 0.000 claims description 8
- 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 claims description 8
- 229960001156 mitoxantrone Drugs 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 230000008030 elimination Effects 0.000 claims description 7
- 238000003379 elimination reaction Methods 0.000 claims description 7
- 230000004083 survival effect Effects 0.000 claims description 7
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine 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 claims description 6
- 208000017604 Hodgkin disease Diseases 0.000 claims description 6
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 6
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 229960000684 cytarabine Drugs 0.000 claims description 6
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 claims description 5
- 108010006654 Bleomycin Proteins 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 229960002756 azacitidine Drugs 0.000 claims description 5
- 229960000397 bevacizumab Drugs 0.000 claims description 5
- 229960003603 decitabine Drugs 0.000 claims 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 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine 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 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 206010005949 Bone cancer Diseases 0.000 claims description 4
- 208000018084 Bone neoplasm Diseases 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin 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=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 206010039491 Sarcoma Diseases 0.000 claims description 4
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 229940009456 adriamycin Drugs 0.000 claims description 4
- 229960001561 bleomycin Drugs 0.000 claims description 4
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound 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)NCCC[S+](C)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=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 239000012649 demethylating agent Substances 0.000 claims description 4
- 201000004101 esophageal cancer Diseases 0.000 claims description 4
- 229960000390 fludarabine Drugs 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000010536 head and neck cancer Diseases 0.000 claims description 4
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 201000002120 neuroendocrine carcinoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 claims description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 3
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 3
- 208000004860 Blast Crisis Diseases 0.000 claims description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 3
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 3
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 3
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 3
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 3
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 3
- 239000003246 corticosteroid Substances 0.000 claims description 3
- 201000003444 follicular lymphoma Diseases 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 229960000908 idarubicin Drugs 0.000 claims description 3
- 230000002071 myeloproliferative effect Effects 0.000 claims description 3
- 229960000688 pomalidomide Drugs 0.000 claims description 3
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 230000009466 transformation Effects 0.000 claims description 3
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims description 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 2
- 229940124291 BTK inhibitor Drugs 0.000 claims description 2
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 claims description 2
- 102100039496 Choline transporter-like protein 4 Human genes 0.000 claims description 2
- 101150002621 EPO gene Proteins 0.000 claims description 2
- 101000889282 Homo sapiens Choline transporter-like protein 4 Proteins 0.000 claims description 2
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 claims description 2
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 claims description 2
- 229940121730 Janus kinase 2 inhibitor Drugs 0.000 claims description 2
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 claims description 2
- 239000012270 PD-1 inhibitor Substances 0.000 claims description 2
- 239000012668 PD-1-inhibitor Substances 0.000 claims description 2
- 229960000975 daunorubicin Drugs 0.000 claims description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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 claims description 2
- 229940121655 pd-1 inhibitor Drugs 0.000 claims description 2
- 229960004528 vincristine Drugs 0.000 claims description 2
- 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 claims description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 2
- 229940124294 CD33 monoclonal antibody Drugs 0.000 claims 2
- 230000001093 anti-cancer Effects 0.000 claims 2
- 229940118364 Bcr-Abl inhibitor Drugs 0.000 claims 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 claims 1
- 102000003702 retinoic acid receptors Human genes 0.000 abstract description 12
- 108090000064 retinoic acid receptors Proteins 0.000 abstract description 12
- 210000004027 cell Anatomy 0.000 description 139
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 64
- 229960001467 bortezomib Drugs 0.000 description 64
- PNAWUIKCVQSLFG-UHFFFAOYSA-N 4-[(4-chloro-3-hydroxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]-2,6-difluorobenzoic acid Chemical compound C1=C2C(C)(C)CCC(C)(C)C2=C(Cl)C(O)=C1C(=O)NC1=CC(F)=C(C(O)=O)C(F)=C1 PNAWUIKCVQSLFG-UHFFFAOYSA-N 0.000 description 56
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 56
- 239000003795 chemical substances by application Substances 0.000 description 37
- 210000002536 stromal cell Anatomy 0.000 description 34
- 230000014509 gene expression Effects 0.000 description 33
- 230000004069 differentiation Effects 0.000 description 30
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 28
- 229910052697 platinum Inorganic materials 0.000 description 28
- 230000000694 effects Effects 0.000 description 25
- 150000004492 retinoid derivatives Chemical class 0.000 description 25
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 23
- 229930002330 retinoic acid Natural products 0.000 description 22
- 230000004044 response Effects 0.000 description 19
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 17
- 239000008194 pharmaceutical composition Substances 0.000 description 16
- 238000002560 therapeutic procedure Methods 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 15
- 244000060234 Gmelina philippensis Species 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 14
- 108010022037 Retinoic Acid 4-Hydroxylase Proteins 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 230000003076 paracrine Effects 0.000 description 14
- 210000003719 b-lymphocyte Anatomy 0.000 description 13
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 12
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 12
- 102100033912 Retinoic acid receptor gamma Human genes 0.000 description 12
- 108091008760 retinoic acid receptors γ Proteins 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 102100033909 Retinoic acid receptor beta Human genes 0.000 description 11
- 229940123237 Taxane Drugs 0.000 description 11
- 230000003021 clonogenic effect Effects 0.000 description 11
- 108091008761 retinoic acid receptors β Proteins 0.000 description 11
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 11
- 239000013598 vector Substances 0.000 description 11
- 230000029918 bioluminescence Effects 0.000 description 10
- 238000005415 bioluminescence Methods 0.000 description 10
- 230000003247 decreasing effect Effects 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
- 230000012010 growth Effects 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 210000004180 plasmocyte Anatomy 0.000 description 10
- 108090000031 Hedgehog Proteins Proteins 0.000 description 9
- 102000003693 Hedgehog Proteins Human genes 0.000 description 9
- 229960005277 gemcitabine Drugs 0.000 description 9
- 230000001404 mediated effect Effects 0.000 description 9
- 230000003827 upregulation Effects 0.000 description 9
- 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 8
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 229960004117 capecitabine Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 8
- 230000011664 signaling Effects 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 229960002066 vinorelbine Drugs 0.000 description 8
- GBABOYUKABKIAF-GHYRFKGUSA-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-GHYRFKGUSA-N 0.000 description 8
- LHUPKWKWYWOMSK-UHFFFAOYSA-N 4-[2-[4-(4-ethylphenyl)-2,2-dimethylthiochromen-6-yl]ethynyl]benzoic acid Chemical compound C1=CC(CC)=CC=C1C1=CC(C)(C)SC2=CC=C(C#CC=3C=CC(=CC=3)C(O)=O)C=C12 LHUPKWKWYWOMSK-UHFFFAOYSA-N 0.000 description 7
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 7
- 241000282414 Homo sapiens Species 0.000 description 7
- 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 7
- 230000006907 apoptotic process Effects 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229960002949 fluorouracil Drugs 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) 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 7
- 230000007246 mechanism Effects 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 231100000419 toxicity Toxicity 0.000 description 7
- 230000001988 toxicity Effects 0.000 description 7
- 239000000439 tumor marker Substances 0.000 description 7
- 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 6
- 239000005557 antagonist Substances 0.000 description 6
- 230000001413 cellular effect Effects 0.000 description 6
- 230000001767 chemoprotection Effects 0.000 description 6
- 238000002512 chemotherapy Methods 0.000 description 6
- 238000000684 flow cytometry Methods 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 229960004768 irinotecan Drugs 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 229960000575 trastuzumab Drugs 0.000 description 6
- 229960001727 tretinoin Drugs 0.000 description 6
- 229960003048 vinblastine Drugs 0.000 description 6
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine 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=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 6
- 101710156077 DNA damage-inducible transcript 3 protein Proteins 0.000 description 5
- 102100029145 DNA damage-inducible transcript 3 protein Human genes 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 108010050904 Interferons Proteins 0.000 description 5
- 102000014150 Interferons Human genes 0.000 description 5
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 5
- 229930182816 L-glutamine Natural products 0.000 description 5
- 108010090920 Proto-Oncogene Proteins c-bcl-6 Proteins 0.000 description 5
- 102000013538 Proto-Oncogene Proteins c-bcl-6 Human genes 0.000 description 5
- 229960002932 anastrozole Drugs 0.000 description 5
- 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 5
- 239000002552 dosage form Substances 0.000 description 5
- 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 5
- 239000008273 gelatin Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 230000009459 hedgehog signaling Effects 0.000 description 5
- 230000002489 hematologic effect Effects 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 229960003881 letrozole Drugs 0.000 description 5
- 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 5
- 238000005259 measurement Methods 0.000 description 5
- 230000004060 metabolic process Effects 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 230000001681 protective effect Effects 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 230000035945 sensitivity Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 230000003442 weekly effect Effects 0.000 description 5
- 206010061818 Disease progression Diseases 0.000 description 4
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 4
- 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 4
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000000540 analysis of variance Methods 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000005750 disease progression Effects 0.000 description 4
- 229960001433 erlotinib Drugs 0.000 description 4
- 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 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 229960001842 estramustine Drugs 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 239000003446 ligand Substances 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
- 238000012423 maintenance Methods 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 4
- 229960001756 oxaliplatin Drugs 0.000 description 4
- 229960002087 pertuzumab Drugs 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 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 4
- 238000011002 quantification Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000035882 stress Effects 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 230000004906 unfolded protein response Effects 0.000 description 4
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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 3
- SZWKGOZKRMMLAJ-UHFFFAOYSA-N 4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1C(=O)NC1=CC=C(C(O)=O)C=C1 SZWKGOZKRMMLAJ-UHFFFAOYSA-N 0.000 description 3
- 101500021166 Aplysia californica Myomodulin-B Proteins 0.000 description 3
- 108010051219 Cre recombinase Proteins 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 238000001061 Dunnett's test Methods 0.000 description 3
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 108010000817 Leuprolide Proteins 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol 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 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 108010009975 Positive Regulatory Domain I-Binding Factor 1 Proteins 0.000 description 3
- 102000009844 Positive Regulatory Domain I-Binding Factor 1 Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 3
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 3
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 3
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 101150063416 add gene Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000001772 blood platelet Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 229960005395 cetuximab Drugs 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 239000003636 conditioned culture medium Substances 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229960001904 epirubicin Drugs 0.000 description 3
- 239000012737 fresh medium Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 229940075628 hypomethylating agent Drugs 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 229960002014 ixabepilone Drugs 0.000 description 3
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 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
- 229960004338 leuprorelin Drugs 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 210000005087 mononuclear cell Anatomy 0.000 description 3
- 229940127084 other anti-cancer agent Drugs 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 239000013610 patient sample Substances 0.000 description 3
- 229960005079 pemetrexed Drugs 0.000 description 3
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 150000003058 platinum compounds Chemical class 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000009877 rendering Methods 0.000 description 3
- 230000001177 retroviral effect Effects 0.000 description 3
- 239000002356 single layer Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229940083542 sodium Drugs 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229950006050 spiromustine Drugs 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical group C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 description 3
- 229960001603 tamoxifen Drugs 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol 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 3
- 210000001519 tissue Anatomy 0.000 description 3
- HZSBSRAVNBUZRA-RQDPQJJXSA-J (1r,2r)-cyclohexane-1,2-diamine;tetrachloroplatinum(2+) Chemical compound Cl[Pt+2](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N HZSBSRAVNBUZRA-RQDPQJJXSA-J 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,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-DOUNNPEJSA-N 0.000 description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-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 2
- 108091032973 (ribonucleotides)n+m Proteins 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
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- OOMDVERDMZLRFX-UHFFFAOYSA-N 2,2-bis(aminomethyl)propane-1,3-diol;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound [Pt].NCC(CN)(CO)CO.OC(=O)C1(C(O)=O)CCC1 OOMDVERDMZLRFX-UHFFFAOYSA-N 0.000 description 2
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 2
- 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 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
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-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
- PZYFNWUXYUMHGR-UHFFFAOYSA-N 4-[1-hydroxy-3-(3-hydroxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)-3-oxoprop-1-enyl]benzoic acid Chemical compound OC=1C=C2C(C)(C)CCC(C)(C)C2=CC=1C(=O)C=C(O)C1=CC=C(C(O)=O)C=C1 PZYFNWUXYUMHGR-UHFFFAOYSA-N 0.000 description 2
- YXHLJMWYDTXDHS-IRFLANFNSA-N 7-aminoactinomycin 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)=C(N)C=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 YXHLJMWYDTXDHS-IRFLANFNSA-N 0.000 description 2
- 108700012813 7-aminoactinomycin D Proteins 0.000 description 2
- RTHKPHCVZVYDFN-UHFFFAOYSA-N 9-amino-5-(2-aminopyrimidin-4-yl)pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-ol Chemical compound NC1=NC=CC(C=2C3=C(O)C=CN=C3N3C(N)=NC=CC3=2)=N1 RTHKPHCVZVYDFN-UHFFFAOYSA-N 0.000 description 2
- 229940126069 ALK kinase inhibitor Drugs 0.000 description 2
- 101150000157 ARHGEF1 gene Proteins 0.000 description 2
- 108020002663 Aldehyde Dehydrogenase Proteins 0.000 description 2
- 102000005369 Aldehyde Dehydrogenase Human genes 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-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 2
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 2
- 206010058354 Bronchioloalveolar carcinoma Diseases 0.000 description 2
- CIUUIPMOFZIWIZ-UHFFFAOYSA-N Bropirimine Chemical compound NC1=NC(O)=C(Br)C(C=2C=CC=CC=2)=N1 CIUUIPMOFZIWIZ-UHFFFAOYSA-N 0.000 description 2
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 2
- LDZJNMJIPNOYGA-UHFFFAOYSA-N C1=C(OC(C)=O)C(OC)=CC=C1C1=C2C3=CC(OC)=C(OC(C)=O)C=C3C=CN2C2=C1C(C=C(OC)C(OC(C)=O)=C1)=C1OC2=O Chemical compound C1=C(OC(C)=O)C(OC)=CC=C1C1=C2C3=CC(OC)=C(OC(C)=O)C=C3C=CN2C2=C1C(C=C(OC)C(OC(C)=O)=C1)=C1OC2=O LDZJNMJIPNOYGA-UHFFFAOYSA-N 0.000 description 2
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 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 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 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
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 2
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 2
- 108010078049 Interferon alpha-2 Proteins 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 239000007760 Iscove's Modified Dulbecco's Medium Substances 0.000 description 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229930126263 Maytansine Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 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
- 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
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 102000012850 Patched-1 Receptor Human genes 0.000 description 2
- 108010065129 Patched-1 Receptor Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone 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 2
- 229940079156 Proteasome inhibitor Drugs 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 108010038912 Retinoid X Receptors Proteins 0.000 description 2
- 102000034527 Retinoid X Receptors Human genes 0.000 description 2
- OTKJDMGTUTTYMP-ROUUACIJSA-N Safingol ( L-threo-sphinganine) Chemical compound CCCCCCCCCCCCCCC[C@H](O)[C@@H](N)CO OTKJDMGTUTTYMP-ROUUACIJSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 102000036693 Thrombopoietin Human genes 0.000 description 2
- 108010041111 Thrombopoietin Proteins 0.000 description 2
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 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
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 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
- 229960004176 aclarubicin Drugs 0.000 description 2
- SMPZPKRDRQOOHT-UHFFFAOYSA-N acronycine Chemical compound CN1C2=CC=CC=C2C(=O)C2=C1C(C=CC(C)(C)O1)=C1C=C2OC SMPZPKRDRQOOHT-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 229950004955 adozelesin Drugs 0.000 description 2
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 108700025316 aldesleukin Proteins 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960000473 altretamine Drugs 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
- 239000003098 androgen Substances 0.000 description 2
- 238000009166 antihormone therapy Methods 0.000 description 2
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 2
- 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 2
- 229950001858 batimastat Drugs 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 229960000997 bicalutamide Drugs 0.000 description 2
- 229950008548 bisantrene Drugs 0.000 description 2
- 229950006844 bizelesin Drugs 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000004820 blood count Methods 0.000 description 2
- 238000009534 blood test Methods 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 229950009494 bropirimine Drugs 0.000 description 2
- 229960001573 cabazitaxel Drugs 0.000 description 2
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 229950007509 carzelesin Drugs 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
- 230000011712 cell development Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- NQGMIPUYCWIEAW-OVCLIPMQSA-N chembl1834105 Chemical compound O/N=C/C1=C(SC)C(OC)=CC(C=2N=CC=CC=2)=N1 NQGMIPUYCWIEAW-OVCLIPMQSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 201000010902 chronic myelomonocytic leukemia Diseases 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000000306 component Substances 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 230000002559 cytogenic effect Effects 0.000 description 2
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 2
- 229950002389 diaziquone Drugs 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 2
- 229950004203 droloxifene Drugs 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229960003649 eribulin Drugs 0.000 description 2
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 description 2
- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 239000000328 estrogen antagonist Substances 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
- 229960000752 etoposide phosphate Drugs 0.000 description 2
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide 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
- 229950011548 fadrozole Drugs 0.000 description 2
- NMUSYJAQQFHJEW-ARQDHWQXSA-N fazarabine 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
- 229950005096 fazarabine Drugs 0.000 description 2
- 229950003662 fenretinide 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
- 239000008103 glucose Substances 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 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 2
- 230000011132 hemopoiesis Effects 0.000 description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 2
- 229950006905 ilmofosine Drugs 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 108010021336 lanreotide Proteins 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 238000000506 liquid--solid chromatography Methods 0.000 description 2
- 101150055452 lsc gene Proteins 0.000 description 2
- 208000016992 lung adenocarcinoma in situ Diseases 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 235000019359 magnesium stearate Nutrition 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
- 229960003951 masoprocol Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine 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
- 229950002676 menogaril Drugs 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
- 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
- 208000024191 minimally invasive lung adenocarcinoma Diseases 0.000 description 2
- 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 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229950008017 ormaplatin Drugs 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229960001744 pegaspargase Drugs 0.000 description 2
- 108010001564 pegaspargase Proteins 0.000 description 2
- VPAWVRUHMJVRHU-VGDKGRGNSA-N perfosfamide Chemical compound OO[C@@H]1CCO[P@@](=O)(N(CCCl)CCCl)N1 VPAWVRUHMJVRHU-VGDKGRGNSA-N 0.000 description 2
- 229950009351 perfosfamide Drugs 0.000 description 2
- NDTYTMIUWGWIMO-UHFFFAOYSA-N perillyl alcohol Chemical compound CC(=C)C1CCC(CO)=CC1 NDTYTMIUWGWIMO-UHFFFAOYSA-N 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229960004293 porfimer sodium Drugs 0.000 description 2
- 229950004406 porfiromycin Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 239000003207 proteasome inhibitor Substances 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 229950010131 puromycin Drugs 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 230000030541 receptor transactivation Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- QXKJWHWUDVQATH-UHFFFAOYSA-N rogletimide Chemical compound C=1C=NC=CC=1C1(CC)CCC(=O)NC1=O QXKJWHWUDVQATH-UHFFFAOYSA-N 0.000 description 2
- 229950005230 rogletimide Drugs 0.000 description 2
- MOCVYVBNJQIVOV-TVQRCGJNSA-N rohitukine 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
- 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 2
- 230000028327 secretion Effects 0.000 description 2
- 229960003440 semustine Drugs 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 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 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 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 2
- 229960001674 tegafur Drugs 0.000 description 2
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 2
- 229960002197 temoporfin Drugs 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide 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
- 229950002376 tirapazamine Drugs 0.000 description 2
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 231100000440 toxicity profile Toxicity 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 229960001099 trimetrexate Drugs 0.000 description 2
- 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 2
- 229960004824 triptorelin Drugs 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
- 230000004614 tumor growth Effects 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 229960002730 vapreotide Drugs 0.000 description 2
- 108700029852 vapreotide Proteins 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 229960003895 verteporfin Drugs 0.000 description 2
- 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 2
- 229960001771 vorozole 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 229950003017 zeniplatin Drugs 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- OPFTUNCRGUEPRZ-UHFFFAOYSA-N (+)-beta-Elemen Natural products CC(=C)C1CCC(C)(C=C)C(C(C)=C)C1 OPFTUNCRGUEPRZ-UHFFFAOYSA-N 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
- OPFTUNCRGUEPRZ-QLFBSQMISA-N (-)-beta-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
- 229930007631 (-)-perillyl alcohol Natural products 0.000 description 1
- OTWVIYXCRFLDJW-QMVMUTFZSA-N (1-hydroxy-1-phosphonooxyethyl) dihydrogen phosphate;rhenium-186 Chemical compound [186Re].OP(=O)(O)OC(O)(C)OP(O)(O)=O OTWVIYXCRFLDJW-QMVMUTFZSA-N 0.000 description 1
- FXUAIOOAOAVCGD-DCDLSZRSSA-N (1s,2r,8r)-1,2,3,5,6,7,8,8a-octahydroindolizine-1,2,8-triol Chemical compound C1CC[C@@H](O)C2[C@H](O)[C@H](O)CN21 FXUAIOOAOAVCGD-DCDLSZRSSA-N 0.000 description 1
- MNHVIVWFCMBFCV-AVGNSLFASA-N (2S)-2-[[(2S)-2-[[(4S)-4-amino-4-carboxybutanoyl]amino]-6-diazo-5-oxohexanoyl]amino]-6-diazo-5-oxohexanoic acid Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CCC(=O)C=[N+]=[N-])C(=O)N[C@@H](CCC(=O)C=[N+]=[N-])C(O)=O MNHVIVWFCMBFCV-AVGNSLFASA-N 0.000 description 1
- MXABZXILAJGOTL-AUYMZICSSA-N (2S)-N-[(2S)-1-[(2S)-1-[(2S,3S)-1-[(2S)-1-[2-[(2S)-1,3-dihydroxy-1-[(E)-1-hydroxy-1-[(2S,3S)-1-hydroxy-3-methyl-1-[[(2Z,6S,9S,12R)-5,8,11-trihydroxy-9-(2-methylpropyl)-6-propan-2-yl-1-thia-4,7,10-triazacyclotrideca-2,4,7,10-tetraen-12-yl]imino]pentan-2-yl]iminobut-2-en-2-yl]iminopropan-2-yl]imino-2-hydroxyethyl]imino-1,5-dihydroxy-5-iminopentan-2-yl]imino-1-hydroxy-3-methylpentan-2-yl]imino-1-hydroxy-3-methylbutan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]-2-[[(2S)-2-[[(2S)-2-[[(Z)-2-[[(2S)-2-[[(Z)-2-[[(2S)-2-[[[(2S)-1-[(Z)-2-[[(2S)-2-(dimethylamino)-1-hydroxypropylidene]amino]but-2-enoyl]pyrrolidin-2-yl]-hydroxymethylidene]amino]-1-hydroxypropylidene]amino]-1-hydroxybut-2-enylidene]amino]-1-hydroxy-3-phenylpropylidene]amino]-1-hydroxybut-2-enylidene]amino]-1-hydroxy-3-methylbutylidene]amino]-1-hydroxypropylidene]amino]pentanediimidic acid Chemical compound CC[C@H](C)[C@H](\N=C(/O)[C@@H](\N=C(/O)[C@H](Cc1ccccc1)\N=C(/O)[C@H](CCC(O)=N)\N=C(/O)[C@H](C)\N=C(/O)[C@@H](\N=C(/O)\C(=C\C)\N=C(/O)[C@H](Cc1ccccc1)\N=C(/O)\C(=C\C)\N=C(/O)[C@H](C)\N=C(/O)[C@@H]1CCCN1C(=O)\C(=C\C)\N=C(/O)[C@H](C)N(C)C)C(C)C)C(C)C)C(\O)=N\[C@@H](CCC(O)=N)C(\O)=N\C\C(O)=N\[C@@H](CO)C(\O)=N\C(=C\C)\C(\O)=N\[C@@H]([C@@H](C)CC)C(\O)=N\[C@H]1CS\C=C/N=C(O)\[C@@H](\N=C(O)/[C@H](CC(C)C)\N=C1\O)C(C)C MXABZXILAJGOTL-AUYMZICSSA-N 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-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
- 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
- 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-WLEIXIPESA-N (2r)-n-[(2s)-5-amino-1-[[(2r,3r)-1-[[(3s,6z,9s,12r,15r,18r,19s)-9-benzyl-15-[(2r)-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-WLEIXIPESA-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
- NOENHWMKHNSHGX-IZOOSHNJSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-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)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 NOENHWMKHNSHGX-IZOOSHNJSA-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
- 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
- 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
- HJNZCKLMRAOTMA-BRBGIFQRSA-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-(2-methyl-1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-hydr Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(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=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=C(C)NC2=CC=CC=C12 HJNZCKLMRAOTMA-BRBGIFQRSA-N 0.000 description 1
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 1
- RDIMTXDFGHNINN-UHFFFAOYSA-N (3R,9R,10R)-1-heptadecen-4,6-diyne-3,9,10-triol Natural products CCCCCCCC(O)C(O)CC#CC#CC(O)C=C RDIMTXDFGHNINN-UHFFFAOYSA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- TVIRNGFXQVMMGB-OFWIHYRESA-N (3s,6r,10r,13e,16s)-16-[(2r,3r,4s)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone 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](O)[C@@H](Cl)C=2C=CC=CC=2)C/C=C/C(=O)N1 TVIRNGFXQVMMGB-OFWIHYRESA-N 0.000 description 1
- FRCJDPPXHQGEKS-BCHFMIIMSA-N (4S,5R)-N-[4-[(2,3-dihydroxybenzoyl)amino]butyl]-N-[3-[(2,3-dihydroxybenzoyl)amino]propyl]-2-(2-hydroxyphenyl)-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxamide Chemical compound C[C@H]1OC(=N[C@@H]1C(=O)N(CCCCNC(=O)c1cccc(O)c1O)CCCNC(=O)c1cccc(O)c1O)c1ccccc1O FRCJDPPXHQGEKS-BCHFMIIMSA-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
- 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
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (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-5,8,11,14,17-p 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=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 PUDHBTGHUJUUFI-SCTWWAJVSA-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
- ANVAOWXLWRTKGA-NTXLUARGSA-N (6'R)-beta,epsilon-carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=CCCC1(C)C ANVAOWXLWRTKGA-NTXLUARGSA-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
- GYPCWHHQAVLMKO-XXKQIVDLSA-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;hydrochloride Chemical group 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\N=C1CC(C)(C)N(O)C(C)(C)C1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GYPCWHHQAVLMKO-XXKQIVDLSA-N 0.000 description 1
- RCFNNLSZHVHCEK-YGCMNLPTSA-N (7s,9s)-7-[(2s,4r,6s)-4-amino-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;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(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 RCFNNLSZHVHCEK-YGCMNLPTSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-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
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- MHFRGQHAERHWKZ-HHHXNRCGSA-N (R)-edelfosine Chemical compound CCCCCCCCCCCCCCCCCCOC[C@@H](OC)COP([O-])(=O)OCC[N+](C)(C)C MHFRGQHAERHWKZ-HHHXNRCGSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 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
- JCIIKRHCWVHVFF-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine;hydrochloride Chemical compound Cl.NC1=NC=NS1 JCIIKRHCWVHVFF-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
- 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
- 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
- ZKFNOUUKULVDOB-UHFFFAOYSA-N 1-amino-1-phenylmethyl phosphonic acid Chemical compound OP(=O)(O)C(N)C1=CC=CC=C1 ZKFNOUUKULVDOB-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- CNQCTSLNJJVSAU-UHFFFAOYSA-N 132937-89-4 Chemical compound O.Cl.Cl.Cl.Cl.OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO.OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO CNQCTSLNJJVSAU-UHFFFAOYSA-N 0.000 description 1
- 101710175516 14 kDa zinc-binding protein Proteins 0.000 description 1
- VKDGNNYJFSHYKD-UHFFFAOYSA-N 2,5-diamino-2-(difluoromethyl)pentanoic acid;hydron;chloride Chemical compound Cl.NCCCC(N)(C(F)F)C(O)=O VKDGNNYJFSHYKD-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 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
- PDWUPXJEEYOOTR-UHFFFAOYSA-N 2-[(3-iodophenyl)methyl]guanidine Chemical compound NC(=N)NCC1=CC=CC(I)=C1 PDWUPXJEEYOOTR-UHFFFAOYSA-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
- XXVLKDRPHSFIIB-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 XXVLKDRPHSFIIB-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
- HYHJFNXFVPGMBI-UHFFFAOYSA-N 2-[[2-chloroethyl(nitroso)carbamoyl]-methylamino]acetamide Chemical compound NC(=O)CN(C)C(=O)N(CCCl)N=O HYHJFNXFVPGMBI-UHFFFAOYSA-N 0.000 description 1
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa 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=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-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
- NIXVOFULDIFBLB-QVRNUERCSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purine-6-sulfinamide Chemical compound C12=NC(N)=NC(S(N)=O)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NIXVOFULDIFBLB-QVRNUERCSA-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
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 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
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-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
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-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,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox 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)NCCC[S+](C)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)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-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
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-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
- JARCFMKMOFFIGZ-UHFFFAOYSA-N 4,6-dioxo-n-phenyl-2-sulfanylidene-1,3-diazinane-5-carboxamide Chemical compound O=C1NC(=S)NC(=O)C1C(=O)NC1=CC=CC=C1 JARCFMKMOFFIGZ-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
- PZYFNWUXYUMHGR-UYRXBGFRSA-N 4-[(z)-1-hydroxy-3-(3-hydroxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)-3-oxoprop-1-enyl]benzoic acid Chemical compound OC=1C=C2C(C)(C)CCC(C)(C)C2=CC=1C(=O)\C=C(/O)C1=CC=C(C(O)=O)C=C1 PZYFNWUXYUMHGR-UYRXBGFRSA-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
- CTSNHMQGVWXIEG-UHFFFAOYSA-N 4-amino-n-(5-chloroquinoxalin-2-yl)benzenesulfonamide Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CN=C(C(Cl)=CC=C2)C2=N1 CTSNHMQGVWXIEG-UHFFFAOYSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide 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
- AKJHMTWEGVYYSE-FXILSDISSA-N 4-hydroxyphenyl retinamide Chemical compound C=1C=C(O)C=CC=1NC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-FXILSDISSA-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
- 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
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- DQOGWKZQQBYYMW-LQGIGNHCSA-N 5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline-2,4-diamine;(2s,3s,4s,5r,6s)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O.COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 DQOGWKZQQBYYMW-LQGIGNHCSA-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
- ATCGGEJZONJOCL-UHFFFAOYSA-N 6-(2,5-dichlorophenyl)-1,3,5-triazine-2,4-diamine Chemical compound NC1=NC(N)=NC(C=2C(=CC=C(Cl)C=2)Cl)=N1 ATCGGEJZONJOCL-UHFFFAOYSA-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
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-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
- LRHPCRBOMKRVOA-UHFFFAOYSA-N 6-[2-(2-hydroxyethylamino)ethyl]indeno[1,2-c]isoquinoline-5,11-dione Chemical compound C12=CC=CC=C2C(=O)N(CCNCCO)C2=C1C(=O)C1=CC=CC=C12 LRHPCRBOMKRVOA-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
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-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
- KABRXLINDSPGDF-UHFFFAOYSA-N 7-bromoisoquinoline Chemical compound C1=CN=CC2=CC(Br)=CC=C21 KABRXLINDSPGDF-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
- JPASRFGVACYSJG-UHFFFAOYSA-N 8,10-dihydroimidazo[4,5-a]acridin-9-one Chemical class N1=C2C=CC3=NC=NC3=C2C=C2C1=CCC(=O)C2 JPASRFGVACYSJG-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- 208000037068 Abnormal Karyotype Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 1
- 206010073128 Anaplastic oligodendroglioma Diseases 0.000 description 1
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide 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
- NQGMIPUYCWIEAW-UHFFFAOYSA-N Antibiotic SF 2738 Natural products COc1cc(nc(C=NO)c1SC)-c1ccccn1 NQGMIPUYCWIEAW-UHFFFAOYSA-N 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 241001550224 Apha Species 0.000 description 1
- MJINRRBEMOLJAK-DCAQKATOSA-N Arg-Lys-Asp 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
- DRCNRVYVCHHIJP-AQBORDMYSA-N Arg-Lys-Glu-Val-Tyr 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
- 239000004475 Arginine Substances 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 108700032558 Aspergillus restrictus MITF Proteins 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 241001263178 Auriparus Species 0.000 description 1
- YOZSEGPJAXTSFZ-ZETCQYMHSA-N Azatyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=N1 YOZSEGPJAXTSFZ-ZETCQYMHSA-N 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 244000056139 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
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 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
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 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
- PPASFTRHCXASPY-UHFFFAOYSA-N Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 Chemical compound Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 PPASFTRHCXASPY-UHFFFAOYSA-N 0.000 description 1
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 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
- DFDTZECTHJFPHE-UHFFFAOYSA-N Crambescidin 816 Natural products C1CC=CC(CC)OC11NC(N23)=NC4(OC(C)CCC4)C(C(=O)OCCCCCCCCCCCCCCCC(=O)N(CCCN)CC(O)CCN)C3(O)CCC2C1 DFDTZECTHJFPHE-UHFFFAOYSA-N 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
- LUEYTMPPCOCKBX-UHFFFAOYSA-N Curacin A Natural products C=CCC(OC)CCC(C)=CC=CCCC=CC1CSC(C2C(C2)C)=N1 LUEYTMPPCOCKBX-UHFFFAOYSA-N 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- 102000009508 Cyclin-Dependent Kinase Inhibitor p16 Human genes 0.000 description 1
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 description 1
- QASFUMOKHFSJGL-LAFRSMQTSA-N Cyclopamine Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H](CC2=C3C)[C@@H]1[C@@H]2CC[C@@]13O[C@@H]2C[C@H](C)CN[C@H]2[C@H]1C QASFUMOKHFSJGL-LAFRSMQTSA-N 0.000 description 1
- 102000004328 Cytochrome P-450 CYP3A Human genes 0.000 description 1
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 102000011108 Cytochrome P450 Family 26 Human genes 0.000 description 1
- 108010037848 Cytochrome P450 Family 26 Proteins 0.000 description 1
- PQNNIEWMPIULRS-UHFFFAOYSA-N Cytostatin Natural products CC=CC=CC=CC(O)C(C)C(OP(O)(O)=O)CCC(C)C1OC(=O)C=CC1C PQNNIEWMPIULRS-UHFFFAOYSA-N 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- SPKNARKFCOPTSY-UHFFFAOYSA-N D-asperlin Natural products CC1OC1C1C(OC(C)=O)C=CC(=O)O1 SPKNARKFCOPTSY-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- GJKXGJCSJWBJEZ-XRSSZCMZSA-N Deslorelin 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
- 235000019739 Dicalciumphosphate Nutrition 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
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin 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(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 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
- VQNATVDKACXKTF-UHFFFAOYSA-N Duocarmycin SA Natural products COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C(C64CC6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-UHFFFAOYSA-N 0.000 description 1
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- NBEALWAVEGMZQY-UHFFFAOYSA-N Enpromate Chemical compound C=1C=CC=CC=1C(C#C)(C=1C=CC=CC=1)OC(=O)NC1CCCCC1 NBEALWAVEGMZQY-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010092408 Eosinophil Peroxidase Proteins 0.000 description 1
- 102100028471 Eosinophil peroxidase Human genes 0.000 description 1
- VAPSMQAHNAZRKC-PQWRYPMOSA-N Epristeride 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
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 1
- 206010073306 Exposure to radiation Diseases 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 108010029961 Filgrastim Proteins 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 208000009139 Gilbert Disease Diseases 0.000 description 1
- 208000022412 Gilbert syndrome Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102100025506 Glycine cleavage system H protein, mitochondrial Human genes 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101000856845 Homo sapiens Glycine cleavage system H protein, mitochondrial Proteins 0.000 description 1
- 101000746367 Homo sapiens Granulocyte colony-stimulating factor Proteins 0.000 description 1
- 101000687344 Homo sapiens PR domain zinc finger protein 1 Proteins 0.000 description 1
- 101000582950 Homo sapiens Platelet factor 4 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101600089709 Homo sapiens X-box-binding protein 1 (isoform 2) Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- OUBORTRIKPEZMG-UHFFFAOYSA-N INT-2 Chemical compound Nc1c(ncn1-c1ccc(F)cc1)C(=N)C#N OUBORTRIKPEZMG-UHFFFAOYSA-N 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 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
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 101000668058 Infectious salmon anemia virus (isolate Atlantic salmon/Norway/810/9/99) RNA-directed RNA polymerase catalytic subunit Proteins 0.000 description 1
- 108700022013 Insecta cecropin B Proteins 0.000 description 1
- 108010054698 Interferon Alfa-n3 Proteins 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KJQFBVYMGADDTQ-CVSPRKDYSA-N L-buthionine-(S,R)-sulfoximine Chemical compound CCCCS(=N)(=O)CC[C@H](N)C(O)=O KJQFBVYMGADDTQ-CVSPRKDYSA-N 0.000 description 1
- GSDBGCKBBJVPNC-BYPYZUCNSA-N L-lombricine 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
- 239000002146 L01XE16 - Crizotinib 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
- ZHTRILQJTPJGNK-UHFFFAOYSA-N Leinamycin Natural products C1CC(C)=CC(O)C(=O)C=CC=CC(N=2)=CSC=2C(C)NC(=O)CC21S(=O)SC(=O)C2(C)O ZHTRILQJTPJGNK-UHFFFAOYSA-N 0.000 description 1
- 108010062867 Lenograstim Proteins 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- LMVRPBWWHMVLPC-KBPJCXPTSA-N Leptolstatin Natural products CC(CC=CC(=CC(C)C(=O)C(C)C(O)C(C)CC(=CCO)C)C)C=C(C)/C=C/C1CC=CC(=O)O1 LMVRPBWWHMVLPC-KBPJCXPTSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010024404 Leukostasis Diseases 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 208000008771 Lymphadenopathy Diseases 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- BLOFGONIVNXZME-UHFFFAOYSA-N Mannostatin A Natural products CSC1C(N)C(O)C(O)C1O BLOFGONIVNXZME-UHFFFAOYSA-N 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
- 102100025169 Max-binding protein MNT Human genes 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 108700021154 Metallothionein 3 Proteins 0.000 description 1
- 102100028708 Metallothionein-3 Human genes 0.000 description 1
- 206010050513 Metastatic renal cell carcinoma Diseases 0.000 description 1
- 108091092878 Microsatellite Proteins 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- HFPXYDFQVINJBV-UHFFFAOYSA-N Mycaperoxide B Natural products O1OC(C(C)C(O)=O)CCC1(C)CCC1(O)C2(C)CCCC(C)(C)C2CCC1C HFPXYDFQVINJBV-UHFFFAOYSA-N 0.000 description 1
- USVMJSALORZVDV-SDBHATRESA-N N(6)-(Delta(2)-isopentenyl)adenosine Chemical compound C1=NC=2C(NCC=C(C)C)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O USVMJSALORZVDV-SDBHATRESA-N 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- WUKZPHOXUVCQOR-UHFFFAOYSA-N N-(1-azabicyclo[2.2.2]octan-3-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide Chemical compound C1N(CC2)CCC2C1NC(=O)C1=CC(Cl)=CC2=C1OCC(=O)N2C WUKZPHOXUVCQOR-UHFFFAOYSA-N 0.000 description 1
- BNQSTAOJRULKNX-UHFFFAOYSA-N N-(6-acetamidohexyl)acetamide Chemical compound CC(=O)NCCCCCCNC(C)=O BNQSTAOJRULKNX-UHFFFAOYSA-N 0.000 description 1
- QJMCKEPOKRERLN-UHFFFAOYSA-N N-3,4-tridhydroxybenzamide Chemical compound ONC(=O)C1=CC=C(O)C(O)=C1 QJMCKEPOKRERLN-UHFFFAOYSA-N 0.000 description 1
- 101710198130 NADPH-cytochrome P450 reductase Proteins 0.000 description 1
- 108010021717 Nafarelin Proteins 0.000 description 1
- GTEXXGIEZVKSLH-UHFFFAOYSA-N Naphterpin Natural products O=C1C2=CC(O)=C(C)C(O)=C2C(=O)C2=C1C1C=C(C)CCC1C(C)(C)O2 GTEXXGIEZVKSLH-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 102400000058 Neuregulin-1 Human genes 0.000 description 1
- 108090000556 Neuregulin-1 Proteins 0.000 description 1
- BUSGWUFLNHIBPT-UHFFFAOYSA-N Nisamycin Natural products O=C1C2OC2C(C=CC=CC=CC(=O)O)(O)C=C1NC(=O)C=CC=CC1CCCCC1 BUSGWUFLNHIBPT-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
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229960005524 O6-benzylguanine Drugs 0.000 description 1
- KRWMERLEINMZFT-UHFFFAOYSA-N O6-benzylguanine Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- VTAZRSXSBIHBMH-UHFFFAOYSA-N Ophiocordin Natural products OC1=CC(C(=O)O)=CC(O)=C1C(=O)C1=C(O)C=CC=C1C(=O)NC1C(OC(=O)C=2C=CC(O)=CC=2)CCCNC1 VTAZRSXSBIHBMH-UHFFFAOYSA-N 0.000 description 1
- LKBBOPGQDRPCDS-UHFFFAOYSA-N Oxaunomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC=C4C(=O)C=3C(O)=C2C(O)C(CC)(O)CC1OC1CC(N)C(O)C(C)O1 LKBBOPGQDRPCDS-UHFFFAOYSA-N 0.000 description 1
- 102100024894 PR domain zinc finger protein 1 Human genes 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- VYOQBYCIIJYKJA-UHFFFAOYSA-N Palauamine Natural products C1N2C(=O)C3=CC=CN3C3N=C(N)NC32C2C1C(CN)C(Cl)C12NC(N)=NC1O VYOQBYCIIJYKJA-UHFFFAOYSA-N 0.000 description 1
- FRCJDPPXHQGEKS-UHFFFAOYSA-N Parabactin Natural products CC1OC(=NC1C(=O)N(CCCCNC(=O)c1cccc(O)c1O)CCCNC(=O)c1cccc(O)c1O)c1ccccc1O FRCJDPPXHQGEKS-UHFFFAOYSA-N 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 229940083963 Peptide antagonist Drugs 0.000 description 1
- APNRZHLOPQFNMR-UHFFFAOYSA-N Phenazinomycin Natural products C12=CC=CC=C2N=C(C(C=CC=2)=O)C=2N1CC=C(C)CCC1C(=C)CCCC1(C)C APNRZHLOPQFNMR-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin 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-HSUXVGOQSA-N 0.000 description 1
- 102000010752 Plasminogen Inactivators Human genes 0.000 description 1
- 108010077971 Plasminogen Inactivators Proteins 0.000 description 1
- 102100030304 Platelet factor 4 Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000007048 Polymyalgia Rheumatica 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
- 208000026149 Primary peritoneal carcinoma Diseases 0.000 description 1
- 102100032420 Protein S100-A9 Human genes 0.000 description 1
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 1
- 101710161390 Protein patched homolog 1 Proteins 0.000 description 1
- 102100028680 Protein patched homolog 1 Human genes 0.000 description 1
- PICZCWCKOLHDOJ-UHFFFAOYSA-N Pseudoaxinellin Natural products N1C(=O)C2CCCN2C(=O)C(CC(N)=O)NC(=O)C(C(C)C)NC(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C(C(C)C)NC(=O)C1CC1=CC=CC=C1 PICZCWCKOLHDOJ-UHFFFAOYSA-N 0.000 description 1
- XESARGFCSKSFID-UHFFFAOYSA-N Pyrazofurin Natural products OC1=C(C(=O)N)NN=C1C1C(O)C(O)C(CO)O1 XESARGFCSKSFID-UHFFFAOYSA-N 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 102000003901 Ras GTPase-activating proteins Human genes 0.000 description 1
- 108090000231 Ras GTPase-activating proteins Proteins 0.000 description 1
- 229940078123 Ras inhibitor Drugs 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 102000012211 Retinoic Acid 4-Hydroxylase Human genes 0.000 description 1
- 102000026043 Retinoid X Receptor alpha Human genes 0.000 description 1
- 108010066463 Retinoid X Receptor alpha Proteins 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- 108010005173 SERPIN-B5 Proteins 0.000 description 1
- 101000767160 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Intracellular protein transport protein USO1 Proteins 0.000 description 1
- YADVRLOQIWILGX-MIWLTHJTSA-N Sarcophytol A 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
- 206010070834 Sensitisation Diseases 0.000 description 1
- 102100030333 Serpin B5 Human genes 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- OCOKWVBYZHBHLU-UHFFFAOYSA-N Sobuzoxane 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
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 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
- UIRKNQLZZXALBI-UHFFFAOYSA-N Squalamine Natural products OC1CC2CC(NCCCNCCCCN)CCC2(C)C2C1C1CCC(C(C)CCC(C(C)C)OS(O)(=O)=O)C1(C)CC2 UIRKNQLZZXALBI-UHFFFAOYSA-N 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- WXZSUBHBYQYTNM-UHFFFAOYSA-N Tetrazomine Natural products C1=CC=2CC(N34)C(N5C)C(CO)CC5C4OCC3C=2C(OC)=C1NC(=O)C1NCCCC1O WXZSUBHBYQYTNM-UHFFFAOYSA-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
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-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
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 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
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 1
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 206010047626 Vitamin D Deficiency Diseases 0.000 description 1
- 108010035430 X-Box Binding Protein 1 Proteins 0.000 description 1
- 102100038151 X-box-binding protein 1 Human genes 0.000 description 1
- 102300064638 X-box-binding protein 1 isoform 2 Human genes 0.000 description 1
- 101001060278 Xenopus laevis Fibroblast growth factor 3 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
- 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
- ZZWKZQDOSJAGGF-VRSYWUPDSA-N [(1s,2e,7s,10e,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-VRSYWUPDSA-N 0.000 description 1
- VUPBDWQPEOWRQP-RTUCOMKBSA-N [(2R,3S,4S,5R,6R)-2-[(2R,3S,4S,5S,6S)-2-[(1S,2S)-3-[[(2R,3S)-5-[[(2S,3R)-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]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-5-oxopentan-2-yl]amino]-2-[[6-amino-2-[(1S)-3-amino-1-[[(2S)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-1-(1H-imidazol-5-yl)-3-oxopropoxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl] carbamate Chemical compound C[C@@H](O)[C@H](NC(=O)C[C@H](O)[C@@H](C)NC(=O)[C@@H](NC(=O)c1nc(nc(N)c1C)[C@H](CC(N)=O)NC[C@H](N)C(N)=O)[C@H](O[C@@H]1O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](OC(N)=O)[C@@H]1O)c1cnc[nH]1)C(=O)NC(O[C@@H]1O[C@@H](C)[C@@H](N)[C@@H](O)[C@H]1O)C(O)c1nc(cs1)-c1nc(cs1)C(=O)NCCCC(N)CC(=O)NCCCNCCCCN VUPBDWQPEOWRQP-RTUCOMKBSA-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
- IVCRCPJOLWECJU-XQVQQVTHSA-N [(7r,8r,9s,10r,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)CC[C@@H]3[C@H]21 IVCRCPJOLWECJU-XQVQQVTHSA-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
- 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
- KMLCRELJHYKIIL-UHFFFAOYSA-N [1-(azanidylmethyl)cyclohexyl]methylazanide;platinum(2+);sulfuric acid Chemical compound [Pt+2].OS(O)(=O)=O.[NH-]CC1(C[NH-])CCCCC1 KMLCRELJHYKIIL-UHFFFAOYSA-N 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
- NAFFDQVVNWTDJD-UHFFFAOYSA-L [4-(azanidylmethyl)oxan-4-yl]methylazanide;cyclobutane-1,1-dicarboxylate;platinum(4+) Chemical compound [Pt+4].[NH-]CC1(C[NH-])CCOCC1.[O-]C(=O)C1(C([O-])=O)CCC1 NAFFDQVVNWTDJD-UHFFFAOYSA-L 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
- 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
- 229960000853 abiraterone Drugs 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- RUGAHXUZHWYHNG-NLGNTGLNSA-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.CC(O)=O.CC(O)=O.CC(O)=O.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.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 RUGAHXUZHWYHNG-NLGNTGLNSA-N 0.000 description 1
- IGCAUIJHGNYDKE-UHFFFAOYSA-N acetic acid;1,4-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione Chemical compound CC([O-])=O.CC([O-])=O.O=C1C2=CC=CC=C2C(=O)C2=C1C(NCC[NH2+]CCO)=CC=C2NCC[NH2+]CCO IGCAUIJHGNYDKE-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 229950008427 acivicin Drugs 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
- 229950000616 acronine Drugs 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
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- HLAKJNQXUARACO-UHFFFAOYSA-N acylfulvene Natural products CC1(O)C(=O)C2=CC(C)=CC2=C(C)C21CC2 HLAKJNQXUARACO-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 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
- WJSAFKJWCOMTLH-UHFFFAOYSA-N adecypenol Natural products OC1C(O)C(CO)=CC1N1C(NC=NCC2O)=C2N=C1 WJSAFKJWCOMTLH-UHFFFAOYSA-N 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 208000030002 adult glioblastoma Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229950010817 alvocidib Drugs 0.000 description 1
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 1
- 229950010949 ambamustine Drugs 0.000 description 1
- 229950004821 ambomycin Drugs 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 229960002550 amrubicin Drugs 0.000 description 1
- 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 1
- 229960001694 anagrelide 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
- 206010002224 anaplastic astrocytoma Diseases 0.000 description 1
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 108010070670 antarelix Proteins 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
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 102000025171 antigen binding proteins Human genes 0.000 description 1
- 108091000831 antigen binding proteins Proteins 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 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
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010055530 arginyl-tryptophyl-N-methylphenylalanyl-tryptophyl-leucyl-methioninamide Proteins 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- TWHSQQYCDVSBRK-UHFFFAOYSA-N asulacrine Chemical compound C12=CC=CC(C)=C2N=C2C(C(=O)NC)=CC=CC2=C1NC1=CC=C(NS(C)(=O)=O)C=C1OC TWHSQQYCDVSBRK-UHFFFAOYSA-N 0.000 description 1
- 229950011088 asulacrine Drugs 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
- 229950004810 atamestane Drugs 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229950006933 atrimustine Drugs 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 108010093161 axinastatin 1 Proteins 0.000 description 1
- PICZCWCKOLHDOJ-GHTSNYPWSA-N axinastatin 1 Chemical compound C([C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N2CCC[C@H]2C(=O)N1)=O)C(C)C)C(C)C)C(C)C)C1=CC=CC=C1 PICZCWCKOLHDOJ-GHTSNYPWSA-N 0.000 description 1
- 108010093000 axinastatin 2 Proteins 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
- UZCPCRPHNVHKKP-UHFFFAOYSA-N axinastatin 2 Natural products CC(C)CC1NC(=O)C2CCCN2C(=O)C(NC(=O)C(CC(=O)N)NC(=O)C3CCCN3C(=O)C(Cc4ccccc4)NC(=O)C(NC1=O)C(C)C)C(C)C UZCPCRPHNVHKKP-UHFFFAOYSA-N 0.000 description 1
- 108010092978 axinastatin 3 Proteins 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
- RTGMQVUKARGBNM-UHFFFAOYSA-N axinastatin 3 Natural products CCC(C)C1NC(=O)C(CC(C)C)NC(=O)C2CCCN2C(=O)C(NC(=O)C(CC(=O)N)NC(=O)C3CCCN3C(=O)C(Cc4ccccc4)NC1=O)C(C)C RTGMQVUKARGBNM-UHFFFAOYSA-N 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
- 229950005951 azasetron Drugs 0.000 description 1
- HRXVDDOKERXBEY-UHFFFAOYSA-N azatepa Chemical compound C1CN1P(=O)(N1CC1)N(CC)C1=NN=CS1 HRXVDDOKERXBEY-UHFFFAOYSA-N 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
- 150000004200 baccatin III derivatives Chemical class 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
- 239000002585 base Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229950005567 benzodepa Drugs 0.000 description 1
- MMIMIFULGMZVPO-UHFFFAOYSA-N benzyl 3-bromo-2,6-dinitro-5-phenylmethoxybenzoate Chemical compound [O-][N+](=O)C1=C(C(=O)OCC=2C=CC=CC=2)C([N+](=O)[O-])=C(Br)C=C1OCC1=CC=CC=C1 MMIMIFULGMZVPO-UHFFFAOYSA-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
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-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
- 230000007175 bidirectional communication Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- LRCVOOBIVXNBIT-NQUDVWKHSA-N bis[2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] butanedioate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]([C@@H](O)C[C@]23C)[C@@H]1[C@@H]3CC[C@]2(O)C(=O)COC(=O)CCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@H](CCC=3[C@@]4(CCC(=O)C=3)C)[C@@H]4[C@@H](O)C[C@@]21C LRCVOOBIVXNBIT-NQUDVWKHSA-N 0.000 description 1
- 229950002370 bisnafide Drugs 0.000 description 1
- NPSOIFAWYAHWOH-UHFFFAOYSA-N bistratene A Natural products O1C(CC(=O)C=CC)CCC(O2)(O)CC(C)C2CCCNC(=O)C(C)C2OC(CCC(C)C=C(C)C(C)O)CCCCC(C)C1CC(=O)NC2 NPSOIFAWYAHWOH-UHFFFAOYSA-N 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229960004395 bleomycin sulfate Drugs 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- PZOHOALJQOFNTB-UHFFFAOYSA-M brequinar sodium 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
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229950002361 budotitane Drugs 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 229950009908 cactinomycin Drugs 0.000 description 1
- 108700002839 cactinomycin Proteins 0.000 description 1
- 229960002882 calcipotriol Drugs 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
- 229960005084 calcitriol Drugs 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol 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
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- BHRQIJRLOVHRKH-UHFFFAOYSA-L calcium;2-[bis[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;hydron Chemical compound [Ca+2].OC(=O)CN(CC(O)=O)CCN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O BHRQIJRLOVHRKH-UHFFFAOYSA-L 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
- 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
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229950009338 caracemide Drugs 0.000 description 1
- 229950005155 carbetimer Drugs 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 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
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin 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
- 229960005243 carmustine Drugs 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 230000004637 cellular stress Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 201000010039 central nervous system leukemia Diseases 0.000 description 1
- 108700008462 cetrorelix Proteins 0.000 description 1
- 229960003230 cetrorelix Drugs 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
- 229960000541 cetyl alcohol 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
- OWSKEUBOCMEJMI-KPXOXKRLSA-N chembl2105946 Chemical compound [N-]=[N+]=CC(=O)CC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@H](CCC(=O)C=[N+]=[N-])C(O)=O OWSKEUBOCMEJMI-KPXOXKRLSA-N 0.000 description 1
- UKTAZPQNNNJVKR-KJGYPYNMSA-N chembl2368925 Chemical compound C1=CC=C2C(C(O[C@@H]3C[C@@H]4C[C@H]5C[C@@H](N4CC5=O)C3)=O)=CNC2=C1 UKTAZPQNNNJVKR-KJGYPYNMSA-N 0.000 description 1
- ZWVZORIKUNOTCS-OAQYLSRUSA-N chembl401930 Chemical compound C1([C@H](O)CNC2=C(C(NC=C2)=O)C=2NC=3C=C(C=C(C=3N=2)C)N2CCOCC2)=CC=CC(Cl)=C1 ZWVZORIKUNOTCS-OAQYLSRUSA-N 0.000 description 1
- DCKFXSZUWVWFEU-JECTWPLRSA-N chembl499423 Chemical compound O1[C@@H](CC)CCCC[C@]11NC(N23)=N[C@]4(O[C@H](C)CCC4)[C@@H](C(=O)OCCCCCCCCCCCCCCCC(=O)N(CCCN)C[C@@H](O)CCN)[C@@]3(O)CC[C@H]2C1 DCKFXSZUWVWFEU-JECTWPLRSA-N 0.000 description 1
- 239000012829 chemotherapy agent Substances 0.000 description 1
- 108700010039 chimeric receptor Proteins 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
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960004407 chorionic gonadotrophin Drugs 0.000 description 1
- ARUGKOZUKWAXDS-SEWALLKFSA-N cicaprost 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
- 229950000634 cicaprost Drugs 0.000 description 1
- 229950011359 cirolemycin Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- JKNIRLKHOOMGOJ-UHFFFAOYSA-N cladochrome D Natural products COC1=C(CC(C)OC(=O)Oc2ccc(O)cc2)c3c4C(=C(OC)C(=O)c5c(O)cc(OC)c(c45)c6c(OC)cc(O)c(C1=O)c36)CC(C)OC(=O)c7ccc(O)cc7 JKNIRLKHOOMGOJ-UHFFFAOYSA-N 0.000 description 1
- SRJYZPCBWDVSGO-UHFFFAOYSA-N cladochrome E Natural products COC1=CC(O)=C(C(C(OC)=C(CC(C)OC(=O)OC=2C=CC(O)=CC=2)C2=3)=O)C2=C1C1=C(OC)C=C(O)C(C(C=2OC)=O)=C1C=3C=2CC(C)OC(=O)C1=CC=CC=C1 SRJYZPCBWDVSGO-UHFFFAOYSA-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
- 238000009643 clonogenic assay Methods 0.000 description 1
- 231100000096 clonogenic assay Toxicity 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
- 239000011248 coating agent Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229960005537 combretastatin A-4 Drugs 0.000 description 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 1
- 150000004814 combretastatins Chemical class 0.000 description 1
- 238000002591 computed tomography Methods 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
- 238000010924 continuous production Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940109239 creatinine 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
- 229950007258 crisnatol Drugs 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical class 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
- 108010090203 cryptophycin 8 Proteins 0.000 description 1
- QASFUMOKHFSJGL-UHFFFAOYSA-N cyclopamine Natural products C1C=C2CC(O)CCC2(C)C(CC2=C3C)C1C2CCC13OC2CC(C)CNC2C1C QASFUMOKHFSJGL-UHFFFAOYSA-N 0.000 description 1
- PESYEWKSBIWTAK-UHFFFAOYSA-N cyclopenta-1,3-diene;titanium(2+) Chemical compound [Ti+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 PESYEWKSBIWTAK-UHFFFAOYSA-N 0.000 description 1
- 108010041566 cypemycin Proteins 0.000 description 1
- YJTVZHOYBAOUTO-URBBEOKESA-N cytarabine ocfosfate Chemical compound O[C@H]1[C@H](O)[C@@H](COP(O)(=O)OCCCCCCCCCCCCCCCCCC)O[C@H]1N1C(=O)N=C(N)C=C1 YJTVZHOYBAOUTO-URBBEOKESA-N 0.000 description 1
- 229950006614 cytarabine ocfosfate Drugs 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- YCWXIQRLONXJLF-PFFGJIDWSA-N d06307 Chemical compound OS(O)(=O)=O.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.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 YCWXIQRLONXJLF-PFFGJIDWSA-N 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 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
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960005408 deslorelin Drugs 0.000 description 1
- 108700025485 deslorelin Proteins 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 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 1
- VPOCYEOOFRNHNL-RQDPQJJXSA-J dexormaplatin Chemical compound Cl[Pt](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N VPOCYEOOFRNHNL-RQDPQJJXSA-J 0.000 description 1
- 229950001640 dexormaplatin Drugs 0.000 description 1
- 229960000605 dexrazoxane Drugs 0.000 description 1
- SGTNSNPWRIOYBX-HHHXNRCGSA-N dexverapamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCC[C@@](C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-HHHXNRCGSA-N 0.000 description 1
- 229950005878 dexverapamil Drugs 0.000 description 1
- 229950010621 dezaguanine Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- KYHUYMLIVQFXRI-UHFFFAOYSA-N didemnin B Natural products CC1OC(=O)C(CC=2C=CC(OC)=CC=2)N(C)C(=O)C2CCCN2C(=O)C(CC(C)C)NC(=O)C(C)C(=O)C(C(C)C)OC(=O)CC(O)C(C(C)CC)NC(=O)C1NC(=O)C(CC(C)C)N(C)C(=O)C1CCCN1C(=O)C(C)O KYHUYMLIVQFXRI-UHFFFAOYSA-N 0.000 description 1
- 108010061297 didemnins Proteins 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 1
- OTKJDMGTUTTYMP-UHFFFAOYSA-N dihydrosphingosine Natural products CCCCCCCCCCCCCCCC(O)C(N)CO OTKJDMGTUTTYMP-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- CZLKTMHQYXYHOO-QTNFYWBSSA-L disodium;(2s)-2-[(2-phosphonatoacetyl)amino]butanedioic acid Chemical compound [Na+].[Na+].OC(=O)C[C@@H](C(O)=O)NC(=O)CP([O-])([O-])=O CZLKTMHQYXYHOO-QTNFYWBSSA-L 0.000 description 1
- SVJSWELRJWVPQD-KJWOGLQMSA-L disodium;(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]pentanedioate Chemical compound [Na+].[Na+].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 SVJSWELRJWVPQD-KJWOGLQMSA-L 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 229960000735 docosanol Drugs 0.000 description 1
- 229960003413 dolasetron Drugs 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone 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
- 229960004242 dronabinol Drugs 0.000 description 1
- 229950004683 drostanolone propionate Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229950005133 duazomycin Drugs 0.000 description 1
- 229930192837 duazomycin Natural products 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229960005510 duocarmycin SA Drugs 0.000 description 1
- 229950010033 ebselen Drugs 0.000 description 1
- 229950005678 ecomustine Drugs 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate 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
- 229950011461 edelfosine Drugs 0.000 description 1
- 229960001776 edrecolomab Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 229960002046 eflornithine hydrochloride Drugs 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
- 229950005450 emitefur Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 229950010625 enloplatin Drugs 0.000 description 1
- 229950001022 enpromate Drugs 0.000 description 1
- 229960004671 enzalutamide Drugs 0.000 description 1
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 1
- 229940088598 enzyme Drugs 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
- 229950001426 erbulozole 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
- 229960001766 estramustine phosphate sodium Drugs 0.000 description 1
- 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 1
- HYSIJEPDMLSIQJ-UHFFFAOYSA-N ethanolate;1-phenylbutane-1,3-dione;titanium(4+) Chemical compound [Ti+4].CC[O-].CC[O-].CC(=O)[CH-]C(=O)C1=CC=CC=C1.CC(=O)[CH-]C(=O)C1=CC=CC=C1 HYSIJEPDMLSIQJ-UHFFFAOYSA-N 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate 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
- 238000011156 evaluation Methods 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000012997 ficoll-paque Substances 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229950006000 flezelastine Drugs 0.000 description 1
- 229960000961 floxuridine 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
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- 229950005682 flurocitabine Drugs 0.000 description 1
- 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 1
- 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 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229950004217 forfenimex Drugs 0.000 description 1
- 229960004421 formestane 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
- 238000009472 formulation Methods 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
- 229950010404 fostriecin 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
- 229960004783 fotemustine Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229950004410 galocitabine Drugs 0.000 description 1
- 108700032141 ganirelix Proteins 0.000 description 1
- GJNXBNATEDXMAK-PFLSVRRQSA-N ganirelix 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
- 229960003794 ganirelix Drugs 0.000 description 1
- 239000002406 gelatinase inhibitor Substances 0.000 description 1
- 229960005144 gemcitabine hydrochloride Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 210000001102 germinal center b cell Anatomy 0.000 description 1
- 208000024693 gingival disease Diseases 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 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
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 229940005608 hypericin Drugs 0.000 description 1
- BTXNYTINYBABQR-UHFFFAOYSA-N hypericin Chemical compound 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
- PHOKTTKFQUYZPI-UHFFFAOYSA-N hypericin Natural products Cc1cc(O)c2c3C(=O)C(=Cc4c(O)c5c(O)cc(O)c6c7C(=O)C(=Cc8c(C)c1c2c(c78)c(c34)c56)O)O PHOKTTKFQUYZPI-UHFFFAOYSA-N 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- 229960001176 idarubicin hydrochloride Drugs 0.000 description 1
- 229950002248 idoxifene Drugs 0.000 description 1
- TZBDEVBNMSLVKT-UHFFFAOYSA-N idramantone Chemical compound C1C(C2)CC3CC1(O)CC2C3=O TZBDEVBNMSLVKT-UHFFFAOYSA-N 0.000 description 1
- 229950009926 idramantone Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 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
- 229960003696 ilomastat Drugs 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 102000028416 insulin-like growth factor binding Human genes 0.000 description 1
- 108091022911 insulin-like growth factor binding Proteins 0.000 description 1
- 238000011368 intensive chemotherapy Methods 0.000 description 1
- 229960003521 interferon alfa-2a Drugs 0.000 description 1
- 229960003507 interferon alfa-2b Drugs 0.000 description 1
- 229940109242 interferon alfa-n3 Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 1
- 229960003795 iobenguane (123i) Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 1
- 229950000855 iroplact Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229950010984 irsogladine Drugs 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- RWXRJSRJIITQAK-ZSBIGDGJSA-N itasetron 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
- 229950007654 itasetron Drugs 0.000 description 1
- GQWYWHOHRVVHAP-DHKPLNAMSA-N jaspamide Chemical compound C1([C@@H]2NC(=O)[C@@H](CC=3C4=CC=CC=C4NC=3Br)N(C)C(=O)[C@H](C)NC(=O)[C@@H](C)C/C(C)=C/[C@H](C)C[C@@H](OC(=O)C2)C)=CC=C(O)C=C1 GQWYWHOHRVVHAP-DHKPLNAMSA-N 0.000 description 1
- 108010052440 jasplakinolide Proteins 0.000 description 1
- GQWYWHOHRVVHAP-UHFFFAOYSA-N jasplakinolide Natural products C1C(=O)OC(C)CC(C)C=C(C)CC(C)C(=O)NC(C)C(=O)N(C)C(CC=2C3=CC=CC=C3NC=2Br)C(=O)NC1C1=CC=C(O)C=C1 GQWYWHOHRVVHAP-UHFFFAOYSA-N 0.000 description 1
- 108010091711 kahalalide F Proteins 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- 229960001739 lanreotide acetate Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960002618 lenograstim Drugs 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 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
- 229960001614 levamisole Drugs 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
- 229950007056 liarozole Drugs 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012669 liquid formulation Substances 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
- 108010020270 lissoclinamide 7 Proteins 0.000 description 1
- RBBBWKUBQVARPL-UHFFFAOYSA-N lissoclinamide 7 Natural products N1C(=O)C(N=2)CSC=2C(CC=2C=CC=CC=2)NC(=O)C(N=2)CSC=2C(C(C)C)NC(=O)C(C(O2)C)N=C2C2CCCN2C(=O)C1CC1=CC=CC=C1 RBBBWKUBQVARPL-UHFFFAOYSA-N 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 229950000909 lometrexol Drugs 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003538 lonidamine 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
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 229950005634 loxoribine Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005249 lung adenocarcinoma 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
- 230000002101 lytic effect Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229950001474 maitansine Drugs 0.000 description 1
- BLOFGONIVNXZME-YDMGZANHSA-N mannostatin A 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
- 229950008959 marimastat Drugs 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
- 238000004949 mass spectrometry Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 210000003519 mature b lymphocyte Anatomy 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 229960002868 mechlorethamine hydrochloride Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol 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
- 229960004296 megestrol acetate Drugs 0.000 description 1
- 229960003846 melengestrol acetate Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 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 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 230000003340 mental effect Effects 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
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 108700025096 meterelin Proteins 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
- BKBBTCORRZMASO-ZOWNYOTGSA-M methotrexate monosodium Chemical compound [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 BKBBTCORRZMASO-ZOWNYOTGSA-M 0.000 description 1
- 229960003058 methotrexate sodium Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960004503 metoclopramide 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
- 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
- QTFKTBRIGWJQQL-UHFFFAOYSA-N meturedepa Chemical compound C1C(C)(C)N1P(=O)(NC(=O)OCC)N1CC1(C)C QTFKTBRIGWJQQL-UHFFFAOYSA-N 0.000 description 1
- 229950009847 meturedepa Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical class 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
- 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
- 229960003775 miltefosine Drugs 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
- 229950008541 mirimostim Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin 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-BKHRDMLASA-N 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
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 108010026677 mitomalcin Proteins 0.000 description 1
- 229950007612 mitomalcin Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229950001745 mitonafide Drugs 0.000 description 1
- 229950005715 mitosper Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 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 1
- 229960004169 mitoxantrone hydrochloride Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229950008012 mofarotene Drugs 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
- 108010032806 molgramostim Proteins 0.000 description 1
- 229960003063 molgramostim Drugs 0.000 description 1
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- 229950010718 mopidamol Drugs 0.000 description 1
- 230000001002 morphogenetic effect Effects 0.000 description 1
- AARXZCZYLAFQQU-UHFFFAOYSA-N motexafin gadolinium Chemical compound [Gd].CC(O)=O.CC(O)=O.C1=C([N-]2)C(CC)=C(CC)C2=CC(C(=C2C)CCCO)=NC2=CN=C2C=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=NC=C2C(C)=C(CCCO)C1=N2 AARXZCZYLAFQQU-UHFFFAOYSA-N 0.000 description 1
- WIQKYZYFTAEWBF-UHFFFAOYSA-L motexafin lutetium hydrate Chemical compound O.[Lu+3].CC([O-])=O.CC([O-])=O.C1=C([N-]2)C(CC)=C(CC)C2=CC(C(=C2C)CCCO)=NC2=CN=C2C=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=NC=C2C(C)=C(CCCO)C1=N2 WIQKYZYFTAEWBF-UHFFFAOYSA-L 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 229960000951 mycophenolic acid Drugs 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
- 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
- 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
- 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
- UMJJGDUYVQCBMC-UHFFFAOYSA-N n-ethyl-n'-[3-[3-(ethylamino)propylamino]propyl]propane-1,3-diamine Chemical compound CCNCCCNCCCNCCCNCC UMJJGDUYVQCBMC-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
- RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin 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
- 229960002333 nafarelin Drugs 0.000 description 1
- 229960004127 naloxone Drugs 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
- 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
- 229950010676 nartograstim Drugs 0.000 description 1
- 108010032539 nartograstim Proteins 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 229950010159 nemorubicin Drugs 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
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore 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
- 230000001613 neoplastic effect Effects 0.000 description 1
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 1
- 229950010733 neridronic acid Drugs 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
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 206010029410 night sweats Diseases 0.000 description 1
- 230000036565 night sweats Effects 0.000 description 1
- 229960002653 nilutamide Drugs 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
- 229940125745 nitric oxide modulator Drugs 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(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)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 229950011093 onapristone Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 229950006466 osaterone 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
- 230000001582 osteoblastic effect Effects 0.000 description 1
- 229950000370 oxisuran Drugs 0.000 description 1
- 125000005430 oxychloro group Chemical group 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
- 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 pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229960003978 pamidronic acid Drugs 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
- ZCKMUKZQXWHXOF-UHFFFAOYSA-N panaxytriol Natural products CCC(C)C(C)C(C)C(C)C(C)C(O)C(O)CC#CC#CC(O)C=C ZCKMUKZQXWHXOF-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229950003440 panomifene Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 208000012111 paraneoplastic syndrome 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
- 229950000039 peldesine Drugs 0.000 description 1
- 229950006960 peliomycin Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 229960003820 pentosan polysulfate sodium 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
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound 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 QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin 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
- 229960001217 perflubron Drugs 0.000 description 1
- 235000005693 perillyl alcohol Nutrition 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000005426 pharmaceutical component Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- LCADVYTXPLBAGB-GNCBHIOISA-N phenalamide A1 Natural products CC(CO)NC(=O)C(=CC=CC=C/C=C/C(=C/C(C)C(O)C(=CC(C)CCc1ccccc1)C)/C)C LCADVYTXPLBAGB-GNCBHIOISA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229940096826 phenylmercuric acetate Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000010399 physical interaction Effects 0.000 description 1
- RNAICSBVACLLGM-GNAZCLTHSA-N pilocarpine hydrochloride Chemical compound Cl.C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C RNAICSBVACLLGM-GNAZCLTHSA-N 0.000 description 1
- 229960002139 pilocarpine hydrochloride Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- XESARGFCSKSFID-FLLFQEBCSA-N pirazofurin 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
- 229950001030 piritrexim Drugs 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 1
- 229960002169 plerixafor Drugs 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229950008499 plitidepsin Drugs 0.000 description 1
- 108010049948 plitidepsin Proteins 0.000 description 1
- UUSZLLQJYRSZIS-LXNNNBEUSA-N plitidepsin 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(C)=O UUSZLLQJYRSZIS-LXNNNBEUSA-N 0.000 description 1
- JKPDEYAOCSQBSZ-OEUJLIAZSA-N plomestane Chemical compound O=C1CC[C@]2(CC#C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKPDEYAOCSQBSZ-OEUJLIAZSA-N 0.000 description 1
- 229950004541 plomestane Drugs 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 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 1
- 238000009597 pregnancy test Methods 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 229960001586 procarbazine hydrochloride Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect 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
- 210000002307 prostate Anatomy 0.000 description 1
- 230000026938 proteasomal ubiquitin-dependent protein catabolic process Effects 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 239000003881 protein kinase C inhibitor Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 239000003806 protein tyrosine phosphatase inhibitor Substances 0.000 description 1
- SSKVDVBQSWQEGJ-UHFFFAOYSA-N pseudohypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(O)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 SSKVDVBQSWQEGJ-UHFFFAOYSA-N 0.000 description 1
- 239000000784 purine nucleoside phosphorylase inhibitor Substances 0.000 description 1
- MKSVFGKWZLUTTO-FZFAUISWSA-N puromycin dihydrochloride Chemical compound Cl.Cl.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 MKSVFGKWZLUTTO-FZFAUISWSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 229960004432 raltitrexed Drugs 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
- 229950001588 ramosetron Drugs 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000001403 relative X-ray reflectometry Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 229950002225 retelliptine Drugs 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 229960004356 riboprine Drugs 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229950003733 romurtide Drugs 0.000 description 1
- 108700033545 romurtide Proteins 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229950008902 safingol Drugs 0.000 description 1
- 238000009118 salvage therapy Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000007480 sanger sequencing Methods 0.000 description 1
- YADVRLOQIWILGX-UHFFFAOYSA-N sarcophytol N Natural products CC(C)C1=CC=C(C)CCC=C(C)CCC=C(C)CC1O YADVRLOQIWILGX-UHFFFAOYSA-N 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000002491 severe combined immunodeficiency Diseases 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229950009089 simtrazene Drugs 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229950010372 sobuzoxane Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 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
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 1
- 229950004225 sonermin Drugs 0.000 description 1
- 229950004796 sparfosic acid Drugs 0.000 description 1
- 229950009641 sparsomycin 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
- XKLZIVIOZDNKEQ-UHFFFAOYSA-N sparsomycin Natural products CSCS(=O)CC(CO)NC(=O)C=CC1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-UHFFFAOYSA-N 0.000 description 1
- YBZRLMLGUBIIDN-NZSGCTDASA-N spicamycin Chemical compound O1[C@@H](C(O)CO)[C@H](NC(=O)CNC(=O)CCCCCCCCCCCCC(C)C)[C@@H](O)[C@@H](O)[C@H]1NC1=NC=NC2=C1N=CN2 YBZRLMLGUBIIDN-NZSGCTDASA-N 0.000 description 1
- YBZRLMLGUBIIDN-UHFFFAOYSA-N spicamycin Natural products 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
- 108010032486 splenopentin Proteins 0.000 description 1
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 1
- HAOCRCFHEPRQOY-JKTUOYIXSA-N spongistatin-1 Chemical compound C([C@@H]1C[C@@H](C[C@@]2(C[C@@H](O)C[C@@H](C2)\C=C/CCC[C@@H]2[C@H](C)[C@@H](O)C[C@](O2)(O)[C@H]2O)O1)OC)C(=O)[C@@H](C)[C@@H](OC(C)=O)[C@H](C)C(=C)C[C@H](O1)C[C@](C)(O)C[C@@]1(O1)C[C@@H](OC(C)=O)C[C@@H]1CC(=O)O[C@H]1[C@H](O)[C@@H](CC(=C)C(C)[C@H](O)\C=C\C(Cl)=C)O[C@@H]2[C@@H]1C HAOCRCFHEPRQOY-JKTUOYIXSA-N 0.000 description 1
- 229950001248 squalamine Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 230000024642 stem cell division Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin 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
- 108091007196 stromelysin Proteins 0.000 description 1
- 229950007841 sulofenur Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229960005314 suramin Drugs 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
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- VAZAPHZUAVEOMC-UHFFFAOYSA-N tacedinaline Chemical compound C1=CC(NC(=O)C)=CC=C1C(=O)NC1=CC=CC=C1N VAZAPHZUAVEOMC-UHFFFAOYSA-N 0.000 description 1
- 229950002687 talisomycin Drugs 0.000 description 1
- 108700003774 talisomycin Proteins 0.000 description 1
- 108010021891 tallimustine Proteins 0.000 description 1
- 229950005667 tallimustine Drugs 0.000 description 1
- 229950010130 tamibarotene Drugs 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229950010168 tauromustine Drugs 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- 239000003277 telomerase inhibitor Substances 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
- 229960004964 temozolomide Drugs 0.000 description 1
- 229950008703 teroxirone Drugs 0.000 description 1
- 229960005353 testolactone Drugs 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
- 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
- ZCTJIMXXSXQXRI-UHFFFAOYSA-N thaliblastine Natural products CN1CCC2=CC(OC)=C(OC)C3=C2C1CC1=C3C=C(OC)C(OC2=C(CC3C4=CC(OC)=C(OC)C=C4CCN3C)C=C(C(=C2)OC)OC)=C1 ZCTJIMXXSXQXRI-UHFFFAOYSA-N 0.000 description 1
- ZCTJIMXXSXQXRI-KYJUHHDHSA-N thalicarpine Chemical compound CN1CCC2=CC(OC)=C(OC)C3=C2[C@@H]1CC1=C3C=C(OC)C(OC2=C(C[C@H]3C4=CC(OC)=C(OC)C=C4CCN3C)C=C(C(=C2)OC)OC)=C1 ZCTJIMXXSXQXRI-KYJUHHDHSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 108010062880 thiocoraline Proteins 0.000 description 1
- UPGGKUQISSWRJJ-UHFFFAOYSA-N thiocoraline Natural products CN1C(=O)CNC(=O)C(NC(=O)C=2C(=CC3=CC=CC=C3N=2)O)CSC(=O)C(CSC)N(C)C(=O)C(N(C(=O)CNC2=O)C)CSSCC1C(=O)N(C)C(CSC)C(=O)SCC2NC(=O)C1=NC2=CC=CC=C2C=C1O UPGGKUQISSWRJJ-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 206010043554 thrombocytopenia Diseases 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
- 229960004231 thymalfasin Drugs 0.000 description 1
- 108010013515 thymopoietin receptor Proteins 0.000 description 1
- 229950010183 thymotrinan Drugs 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229950011457 tiamiprine Drugs 0.000 description 1
- 229960003723 tiazofurine Drugs 0.000 description 1
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine 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
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- ONYVJPZNVCOAFF-UHFFFAOYSA-N topsentin Natural products Oc1ccc2cc([nH]c2c1)C(=O)c3ncc([nH]3)c4c[nH]c5ccccc45 ONYVJPZNVCOAFF-UHFFFAOYSA-N 0.000 description 1
- 229960005026 toremifene Drugs 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
- 229960004167 toremifene citrate Drugs 0.000 description 1
- 210000003014 totipotent stem cell Anatomy 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 108091006107 transcriptional repressors Proteins 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229950003873 triciribine Drugs 0.000 description 1
- 229960000538 trimetrexate glucuronate Drugs 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 description 1
- WMPQMBUXZHMEFZ-YJPJVVPASA-N turosteride Chemical compound CN([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)N(C(C)C)C(=O)NC(C)C)[C@@]2(C)CC1 WMPQMBUXZHMEFZ-YJPJVVPASA-N 0.000 description 1
- 229950007816 turosteride Drugs 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- SPDZFJLQFWSJGA-UHFFFAOYSA-N uredepa Chemical compound C1CN1P(=O)(NC(=O)OCC)N1CC1 SPDZFJLQFWSJGA-UHFFFAOYSA-N 0.000 description 1
- 229950006929 uredepa Drugs 0.000 description 1
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229950008261 velaresol Drugs 0.000 description 1
- XLQGICHHYYWYIU-UHFFFAOYSA-N veramine Natural products O1C2CC3C4CC=C5CC(O)CCC5(C)C4CC=C3C2(C)C(C)C21CCC(C)CN2 XLQGICHHYYWYIU-UHFFFAOYSA-N 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine 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-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-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-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 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 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- BCXOZISMDZTYHW-IFQBWSDRSA-N vinepidine 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@@H](C2)CC)N2CCC2=C1NC1=CC=CC=C21 BCXOZISMDZTYHW-IFQBWSDRSA-N 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
- 230000003612 virological effect Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- DVPVGSLIUJPOCJ-XXRQFBABSA-N x1j761618a Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.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.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 DVPVGSLIUJPOCJ-XXRQFBABSA-N 0.000 description 1
- 229950005561 zanoterone Drugs 0.000 description 1
- 229950009268 zinostatin Drugs 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
- 150000003952 β-lactams Chemical class 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- CYP26-resistant retinoic acid receptor alpha (RAR ⁇ ) selective agonists Disclosed herein are methods of treating cancer with CYP26-resistant retinoic acid receptor alpha (RAR ⁇ ) selective agonists.
- HSCs Normal hematopoietic stem cells
- CYP26 metabolically inactivates retinoic acid, regulates the exposure of the bone marrow to retinoids.
- This mechanism CPY26-mediated retinoid metabolism is dynamic and used by the bone marrow stroma to match HSC behavior to physiological needs.
- steady state low levels of retinoids in the bone marrow niche maintains HSCs in a quiescent state, while during situations of stress (i.e., exposure to radiation or chemotherapy) higher retinoid levels are maintained to recruit HSCs into cell division and rescue hematopoiesis.
- cancer HSCs are protected from retinoids by stromal CYP26, in a similar fashion to the normal situation.
- stromal CYP26 because of other alterations in the bone marrow niche in hematologic malignancies, such as differences in aldehyde dehydrogenase (ALDH) activity, there exists a therapeutic window for retinoids to be useful in the treatment of hematologic malignancies.
- AML immature acute myeloid leukemia
- ATRA all-trans retinoic acid
- retinoic acid receptor gamma Exposure to pharmacological concentrations of ATRA acting through retinoic acid receptor gamma (RARy), induces CYP26 expression in the bone marrow microenvironment, thus protecting the cancer stem cells therein from retinoid activity.
- RARy retinoic acid receptor gamma
- the use of retinoid analogs which are not inactivated by CYP26 enables such retinoids to terminally differentiate and thus eliminate the cancer HSCs from the protective bone marrow niche. Since such differentiation is mediated by RAR ⁇ , and the use of RAR ⁇ specific analogs, which are CYP26 resistant, enables the therapeutic differentiation-inducing activity without inactivation by the CYP26 enzyme.
- RAR CYP26-resistant, retinoic acid receptor (RAR) alpha (RAR ⁇ ) selective agonists and their use in the treatment of malignancies by acting upon cancer stem cells resident in the bone marrow.
- a hematologic malignancy comprising administering to a subject in need thereof an effective dose of a CYP26-resistant RAR ⁇ selective agonist, whereby as a result of the treatment the tumor burden is reduced in the subject.
- administration of an effective dose of the CYP26-resistant RAR ⁇ selective agonist results in the elimination of minimal residual disease or cancer stem cells from the bone marrow niche of the subject, thereby rendering the subject substantially free of cancer.
- administration of an effective dose of the CYP26-resistant RAR ⁇ selective agonist results in sensitization of minimal residual disease to other anticancer agents, whereby combination of the CYP26-resistant RAR ⁇ selective agonist with other anticancer agents results in elimination of minimal residual disease or cancer stem cells from the bone marrow niche of the subject, thereby rendering the subject substantially free of cancer.
- the cancer stem cell is a hematologic cancer stem cell (HSC).
- HSC hematologic cancer stem cell
- the hematologic malignancy is acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), accelerated CML, CML blast phase (CML-BP), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin’s disease (HD), non-Hodgkin’s lymphoma (NHL), follicular lymphoma, mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma (MM), Waldenstrom’s macroglobulinemia, a myelodysplastic syndrome (MDS), refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), or a my
- the CYP26-resistant RAR ⁇ selective agonist is
- the CYP26-resistant RAR ⁇ selective agonist is tamibarotene (AM80), AM580, or Re 80.
- the subject remains in remission longer than 5 years.
- Also disclosed herein are methods for treating a solid tumor malignancy comprising administering to a subject in need thereof an effective dose of a CYP26-resistant RAR ⁇ selective agonist, and at least one additional anti-cancer agent, whereby as a result of the treatment, the tumor burden is reduced in the subject.
- administering results in the elimination of minimal residual disease or cancer stem cells in the bone marrow niche of the subject, thereby rendering the subject substantially free of cancer.
- the solid tumor malignancy is a type of cancer which typically metastasizes to the bone marrow.
- the additional anti-cancer agent is an agent listed in Table 1.
- the solid tumor malignancy is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, brain cancer, bone cancer, or soft tissue sarcoma.
- the additional anti-cancer agent is selected from the combinations in Table 1.
- the additional anti-cancer agent is trastuzumab, tamoxifen, anastrazole, exemestrane, letrozole, crizotinib, aberatrone, enzalutamide, bicalutemide, bortezomib, or thalidomide.
- the subject remains in remission longer than 1 year, longer than 2 years, longer than 3 years, longer than 4 years, or longer than 5 years.
- the subject remains in remission for at least 1 year (e.g., 1-2 years, 1-3 years, 1-4 years, 1-5 years, 2-3 years, 2-4 years, 2-5 years, 3-4 years, 3-5 years, or 4-5 years).
- 1 year e.g., 1-2 years, 1-3 years, 1-4 years, 1-5 years, 2-3 years, 2-4 years, 2-5 years, 3-4 years, 3-5 years, or 4-5 years.
- the subject remains in remission for 1-2 years, 1-3 years, 1-4 years, or 1-5 years.
- RAR ⁇ retinoic acid receptor alpha
- RAR ⁇ retinoic acid receptor alpha
- RAR ⁇ retinoic acid receptor alpha
- Also disclosed herein are methods for treating multiple myeloma comprising administering to a subject in need thereof an effective dose of a CYP26-resistant retinoic acid receptor alpha (RAR ⁇ ) selective agonist and bortezomib, whereby as a result of the treatment the tumor burden is reduced in the subject.
- RAR ⁇ retinoic acid receptor alpha
- Also disclosed herein are methods for treating multiple myeloma comprising administering to a subject in need thereof an effective dose of a IRX5183 and bortezomib, whereby as a result of the treatment the tumor burden is reduced in the subject.
- FIGS. 1 A-H depicts the relative concentration of plasma markers BCL6 ( FIGS. 1 A and E ), BLIMP-1 ( FIGS. 1 B and F ), XBPS-1 ( FIGS. 1 C and G ), and CHOP ( FIGS. 1 D and H ) and in multiple myeloma (MM) cell lines H929 ( FIGS. 1 A-D ) or CD138+ MM cells from three different patient samples ( FIGS.
- FIGS. 2 A-B depicts the clonogenic recovery (CFU) of H929 cells ( FIG. 2 A ) or cellular recovery of primary CD138+ MM cells from 3 different patient samples ( FIG. 2 B ).
- MM cells were treated with BTZ (2.5 nM) for 48 hours after being incubated for 5 days either in the absence of stroma (Liquid), with or without the pan-RAR inhibitor AGN (1 ⁇ M), or in the presence of BM mesenchymal cells (Stroma), with or without the CYP26 inhibitor R115 (1 ⁇ M) or the CYP26-resistant retinoid IRX (1 ⁇ M).
- Clonogenic or cellular recovery was normalized to each condition in the absence of BTZ.
- FIG. 3 depicts clonogenic recovery of H929 cells treated with BTZ (2.5 nM). MM cells were incubated for 5 days in the absence (Liquid) or presence of BM mesenchymal cells (Stroma), with or without R115 (1 ⁇ M). Following this preincubation, H929 cells were separated from BM stroma, cultured in fresh media for 0 to 48 hours, and then treated with BTZ (2.5 nM) for 48 hours. Clonogenic recovery was normalized to each condition in the absence of BTZ.
- FIGS. 5 A-C depicts the effects of MM cells on the expression of CYP26A1 in BM stroma. Relative quantification of CYP26A1 mRNA in human BM mesenchymal cells incubated for 24 hours either in the absence (Ctrl) or presence (Coculture or Transwell) of MM cells (H929 [ FIG. 5 A ], MM1s [ FIG. 5 B ], U266 [ FIG. 5 C ]). Expression in untreated BM stroma (Ctrl) was arbitrarily set at 1.
- FIGS. 6 A-C depicts the relative quantification of CYP26A1 mRNA in mouse wild type (WT) or Smo-KO BM stroma incubated for 24 hr in the absence (Ctrl) or presence (Coculture or Transwell) of MM cells (H292, MM1s, U266).
- Expression in untreated WT or Smo-KO stroma was arbitrarily set at 1 for the respective treated conditions.
- Data represent the mean ⁇ SEM of 3 independent experiments. *P ⁇ 0.05 and **P ⁇ 0.01, by unpaired, 2-tailed Student’s t test.
- FIG. 7 depicts bioluminescent images of mice showing tumor burden during 4 weeks of treatment with IRX (10 mg/kg), BTZ (0.5 mg/kg), or the combination.
- Anterior tumors consisted of a combination of MM1S luciferase + cells and Smo FI/FI BM stroma cells transduced with a control vector (WT BM stroma).
- Posterior tumors consisted of a combination of MM1S luciferase + cells and Smo FI/FI BM stroma cells transduced with Cre-recombinase (Smo KO BM stroma).
- FIG. 8 depicts the fold change in bioluminescence (photons/second) of tumors during 4 weeks of treatment.
- the change in bioluminescence for each tumor at day 1 was normalized to the change in bioluminescence at day 14 and at the end of treatment (day 28).
- FIGS. 9 A-H depicts the relative quantification of BCL6 (B cell marker), BLIMP, XBP1s, and CHOP (PC markers) in H929 cells ( FIG. 9 A ) and primary CD138+ MM cells ( FIG. 9 B ) from 3 different patient samples incubated for 5 days either in the absence of stroma (Ctrl) or cocultured with WT or Smo-KO stromal cells. Expression in untreated liquid conditions was set at 1. Data represent the mean ⁇ SEM. *P ⁇ 0.05 and **P ⁇ 0.01, by repeated-measures 1-way ANOVA to determine statistical significance between treatment groups; P values were corrected for multiple comparisons using Dunnett’s test.
- BCL6 B cell marker
- BLIMP BLIMP
- XBP1s XBP1s
- CHOP PC markers
- FIGS. 10 A-C depicts stroma blockage of ATRA-mediated, but not AM80- or IRX5183-induced, differentiation and elimination of AML.
- FIG. 10 A CFU experiments with NB4 cells treated with 10 -7 M ATRA, IRX5183, or 10 -8 M AM80;
- FIG. 10 B OCI-AML3 cells and
- FIG. 10 C Kasumi-1 cells treated with 10 -6 M ATRA, IRX5183, or 10 -7 M AM80 showed a decrease in clonogenic growth compared to control with AM80 and IRX5183 both off and on stroma. Data across three independent experiments.
- RAR CYP26-resistant, retinoic acid receptor (RAR) alpha (RAR ⁇ ) selective agonists and their use in the treatment of malignancies by acting upon cancer stem cells resident in the bone marrow.
- cancer stem cells are often biologically distinct from the bulk of differentiated cancer cells that characterize the disease.
- CML chronic myeloid leukemia
- CML stem cells undergo orderly differentiation.
- the bulk of the leukemic mass in CML consists of differentiated blood cells, whereas the rare cells responsible for disease maintenance resemble normal hematopoietic stem cells.
- myeloma which is characterized by neoplastic plasma cells, these cells appear to be terminally differentiated like their normal counterparts.
- the myeloma plasma cells that form the bulk of the tumor arise from a population of less differentiated cancer stem cells that resemble post-germinal center B cells.
- Other cancers including but not limited to, hematological malignancies, myelodysplastic syndrome, breast cancer, prostate cancer, pancreatic cancer, colon cancer, ovarian cancer, melanoma, non-melanoma skin cancers, and brain cancers have been demonstrated to arise from corresponding cancer stem cells.
- CYP26-resistant, RAR ⁇ selective agonists which can act on the cancer stem cells in the bone marrow niche (because they are not inactivated by CYP26) is one such approach.
- effectiveness of therapy with a RAR ⁇ selective agonist disclosed herein leads to a substantial decrease in the number of cancer stem cells in the bone marrow.
- the cancer stem cells can be enumerated by various mechanisms and reduction in their numbers as a result of administration of a CYP26-resistant RAR ⁇ selective agonist measured thereby.
- the cancer stem cells in the bone marrow are reduced by more than about 0.5 log, more than about 1 log, more than about 1.5 log, more than about 2.0 log, more than about 2.5 log, more than about 3.0 log, more than about 3.5 log, more than about 4.0 log, more than about 4.5 log, or more than about 5.0 log.
- RARs nuclear retinoic acid receptors
- RARE RAR response elements
- RXRs retinoid X receptors
- RAR ⁇ agonist is synonymous with “RAR ⁇ selective agonist” and refers to a compound that selectively binds RAR ⁇ .
- selective agonist refers to the discriminatory binding of a RAR ⁇ selective agonist to the indicated target RAR ⁇ such that the RAR ⁇ selective agonist does not substantially bind with non-target receptors like a RAR ⁇ or a RAR ⁇ .
- Binding affinity refers to the length of time a RAR ⁇ selective agonist resides at its a RAR ⁇ binding site, and can be viewed as the strength with which a RAR ⁇ selective agonist binds its a RAR ⁇ .
- Binding specificity is the ability of a RAR ⁇ selective agonist to discriminate between a RAR ⁇ and a receptor that does not contain its binding site, such as, e.g., a RAR ⁇ or a RAR ⁇ .
- One way to measure binding specificity is to compare the association rate of a RAR ⁇ selective agonist for its RAR ⁇ relative to the association rate of a RAR ⁇ agonist for a receptor that does not contain its binding site; for example, comparing the association rate constant of a RAR ⁇ selective agonist for its RAR ⁇ relative to a RAR ⁇ and/or a RAR ⁇ .
- a RAR ⁇ selective agonist will have a ratio of activity at a RAR ⁇ relative to a RAR ⁇ and/or a RAR ⁇ of, e.g., at least 5 times greater, at least 10 times greater, at least 15 times greater, at least 20 times greater or at least 10,000 times greater.
- a RAR pan agonist will have activity at a RAR ⁇ , a RAR ⁇ , and a RAR ⁇ , i.e., similar potency at a RAR ⁇ , a RAR ⁇ , and a RAR ⁇ .
- the binding specificity of a RAR ⁇ selective agonist that selectively binds to a RAR ⁇ can also be characterized as an activity ratio that such a RAR ⁇ selective agonist can exert through binding to its RAR ⁇ relative to a receptor not comprising its binding site, such as, e.g., a RAR ⁇ or a RAR ⁇ .
- a RAR ⁇ selective agonist that selectively binds to a RAR ⁇ has an activity ratio through its RAR ⁇ relative to a receptor not comprising its binding site of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 64:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least 40:1.
- a RAR ⁇ selective agonist that selectively binds to a RAR ⁇ has an activity ratio through its RAR ⁇ relative to a RAR ⁇ and/or a RAR ⁇ of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 64:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least 40:1.
- a RAR ⁇ selective agonist that selectively binds to a RAR ⁇ has an activity ratio through its RAR ⁇ relative to a receptor not comprising its binding site of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least 40:1.
- a RAR ⁇ selective agonist that selectively binds to a RAR ⁇ has an activity ratio through its RAR ⁇ relative to a RAR ⁇ and/or a RAR ⁇ of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least 40:1.
- RAR ⁇ selective agonists useful in the methods disclosed herein are RAR ⁇ selective agonists which are not metabolized by CYP26.
- CYP26 is a cytochrome P450 monooxygenase that metabolizes retinoic acid into inactive or less active substances which can also be readily eliminated from cells and regulates cellular levels of retinoic acid.
- RAR ⁇ selective agonists that are readily metabolized by CYP26 are not within the scope of the present methods.
- a CYP26-resistant RAR ⁇ selective agonist is a compound having the structure of formula I,
- R 1 is H or C 1-6 alkyl
- halogen is F, Cl, Br or I. In some embodiments, of formula I, halogen is F. In some embodiments, of formula I, halogen is Cl. In some embodiments, of formula I, halogen is Br. In some embodiments, of formula I, halogen is I.
- a CYP26-resistant RAR ⁇ selective agonist is a compound having a structure of formula II
- R 1 is H or C 1-6 alkyl.
- a CYP26-resistant RAR ⁇ selective agonist is the compound having the structure of formula III
- a CYP26-resistant RAR ⁇ selective agonist is tamibarotene (AM80; 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid).
- a CYP26-resistant RAR ⁇ selective agonist is AM580 (4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid).
- a CYP26-resistant RAR ⁇ selective agonist is Re 80 (4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid).
- CYP26-resistant refers to RAR ⁇ selective agonists which are not metabolized, degraded, or otherwise inactivated by the CYP26 enzyme and have activity within the bone marrow.
- cancer refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites.
- cancer includes, but is not limited to, solid tumors and hematologic tumors.
- cancer encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels.
- cancer further encompasses primary and metastatic cancers. Included within the term “cancer” are cancer stem cells.
- the cancer is a hematologic malignancy.
- hematologic malignancy include acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), including accelerated CML and CML blast phase (CML-BP), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin’s disease (HD), non-Hodgkin’s lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma (MM), Waldenstrom’s macroglobulinemia, myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), (refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T), and myeloproliferative syndromes.
- AML acute mye
- the RAR ⁇ selective agonist when the cancer is a hematologic malignancy, could be administered either as a stand-alone therapy in the absence of other anti-cancer treatments or in combination with other therapies, including but not limited to those listed below in Table 1.
- the cancer is a solid tumor. In other embodiments, the cancer is a solid tumor which can metastasize to the bone.
- solid tumors that can be treated by the disclosed methods include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors,
- a compound disclosed herein, or a composition comprising such a compound is generally administered to an individual as a pharmaceutical composition.
- Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound as disclosed herein, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, with conventional acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for therapeutic use.
- the term “pharmaceutical composition” and refers to a therapeutically effective concentration of an active compound, such as, e.g., any of the compounds disclosed herein.
- the pharmaceutical composition does not produce an adverse, allergic, or other untoward or unwanted reaction when administered to an individual.
- a pharmaceutical composition disclosed herein is useful for medical and veterinary applications.
- a pharmaceutical composition may be administered to an individual alone, or in combination with other supplementary active compounds, agents, drugs or hormones.
- the pharmaceutical compositions may be manufactured using any of a variety of processes, including, without limitation, conventional mixing, dissolving, granulating, dragée-making, levigating, emulsifying, encapsulating, entrapping, and lyophilizing.
- the pharmaceutical composition can take any of a variety of forms including, without limitation, a sterile solution, suspension, emulsion, lyophilizate, tablet, pill, pellet, capsule, powder, syrup, elixir, or any other dosage form suitable for administration.
- Liquid dosage forms suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethyleneglycol (PEG), glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
- a therapeutically effective amount of a compound disclosed herein typically is between about 0.0001% (w/v) to about 50% (w/v), about 0.001% (w/v) to about 10.0% (w/v), or about 0.01% (w/v) to about 1.0% (w/v).
- Solid dosage forms suitable for oral administration include capsules, tablets, pills, powders and granules.
- the active compound may be admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents
- a pharmaceutical composition disclosed herein can optionally include a pharmaceutically acceptable carrier that facilitates processing of an active compound into pharmaceutically acceptable compositions.
- pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
- the term “pharmacologically acceptable carrier” is synonymous with “pharmacological carrier” and refers to any carrier that has substantially no long term or permanent detrimental effect when administered and encompasses terms such as “pharmacologically acceptable vehicle, stabilizer, diluent, additive, auxiliary, or excipient.”
- a carrier generally is mixed with an active compound or permitted to dilute or enclose the active compound and can be a solid, semi-solid, or liquid agent. It is understood that the active compounds can be soluble or can be delivered as a suspension in the desired carrier or diluent.
- aqueous media such as, e.g., water, saline, glycine, hyaluronic acid and the like
- solid carriers such as, e.g., starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like
- solvents dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient.
- Selection of a pharmacologically acceptable carrier can depend on the mode of administration.
- any pharmacologically acceptable carrier is incompatible with the active compound, its use in pharmaceutically acceptable compositions is contemplated.
- Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7 th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20 th ed. 2000); Goodman & Gilman’s The Pharmacological Basis of Therapeutics (Joel G.
- a pharmaceutical composition disclosed herein can optionally include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like.
- buffers include, without limitation, acetate buffers, borate buffers, citrate buffers, phosphate buffers, neutral buffered saline, and phosphate buffered saline.
- antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.
- Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition, such as, e.g., sodium chlorite and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide.
- Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor.
- the pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical composition useful in the claimed methods.
- administering refers to providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering. Administration includes, but is not limited to, oral administration, nasal administration, pulmonary administration, subcutaneous administration, intravenous administration, intramuscular administration, intratumoral administration, intracavity administration, intravitreal administration, dermal administration, and transdermal administration, etc.
- the disclosed RAR ⁇ selective agonists may be administered at varying therapeutically effective doses to a patient in need thereof.
- the dose administered to a mammal, particularly a human, in the context of the present methods should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
- the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
- a therapeutically effective amount when administering a RAR ⁇ selective agonist disclosed herein to a mammal, a therapeutically effective amount generally may be in the range of about 1 mg/m 2 /day to about 100 mg/m 2 /day.
- an effective amount of a RAR ⁇ selective agonist disclosed herein may be about 5 mg/m 2 /day to about 90 mg/m 2 /day, about 10 mg/m 2 /day to about 80 mg/m 2 /day, about 15 mg/m 2 /day to about 70 mg/m 2 /day, about 20 mg/m 2 /day to about 65 mg/m 2 /day, about 25 mg/m 2 /day to about 60 mg/m 2 /day, or about 30 mg/m 2 /day to about 55 mg/m 2 /day.
- a therapeutically effective amount of a compound or a composition disclosed herein may be at least 10 mg/m 2 /day, at least 15 mg/m 2 /day, at least 20 mg/m 2 /day, at least 25 mg/m 2 /day, at least 30 mg/m 2 /day, at least 35 mg/m 2 /day, at least 40 mg/m 2 /day, at least 45 mg/m 2 /day, at least 50 mg/m 2 /day, at least 55 mg/m 2 /day, at least 60 mg/m 2 /day, at least 65 mg/m 2 /day,or at least 75 mg/m 2 /day.
- a therapeutically effective amount of a RAR ⁇ selective agonist disclosed herein may be at most 15 mg/m 2 /day, at most 20 mg/m 2 /day, at most 25 mg/m 2 /day, at most 30 mg/m 2 /day, at most 35 mg/m 2 /day, at most 40 mg/m 2 /day, at most 45 mg/m 2 /day, at most 50 mg/m 2 /day, at most 55 mg/m 2 /day, at most 60 mg/m 2 /day, at most 65 mg/m 2 /day, at most 70 mg/m 2 /day, at most 80 mg/m 2 /day, at most 90 mg/m 2 /day, or at most 100 mg/m 2 /day.
- Administration may be continuous or intermittent.
- the dosage may also be determined by the timing and frequency of administration.
- the RAR ⁇ selective agonists disclosed herein can be given on a daily, weekly, or monthly basis for a period of time, followed by an optional drug holiday (drug free period) and that this drug administration/drug holiday cycle can be repeated as necessary.
- the RAR ⁇ selective agonist is administered in combination with one or more additional anti-cancer agents.
- Anti-cancer agents include cytotoxic drugs, including, but not limited to, paclitaxel, docetaxel, and the like and mixtures thereof.
- Additional anti-cancer agents include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubic
- the anti-cancer agent includes, but is not limited to: 5-fluorouracil, 20-epi-I,25 dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecypenol, adozelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, anti-dorsalizing morphogenetic protein-1, antiandrogen, prostatic carcinoma, antiestrogen, antineoplaston, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators, apurinic acid
- the anti-cancer agent is one or more of an antracycline (e.g., doxorubicin or epirubicin), cyclophosphamide, a platinum agent (e.g., cisplatin, carboplatin, oxaliplatin), a taxane (e.g., paclitaxel or docetaxel), methotrexate, 5-fluorouracil, trastuxumab, pertuzumab, vinorelbine, capecitabine, gemcitabine, mitoxantrone, ixabepilone, reibulin, an anti-hormone therapy (e.g., tamoxifen, anastrazole, exemestrane, letrozole), etoposide, irinotecan, vinblastine, pemetrexed, bevacizumab, cetuximab, an EGFR inhibitor (e.g., erlotinib), an EML4
- RAR ⁇ selective agonists and additional anti-cancer agents useful in the treatment of cancer are listed below in Table 1.
- the listed drug combinations can be administered at the same time, at different times, in the same composition, in different compositions, in alternating times (1 week of RAR ⁇ selective agonist followed by 1 week of another anti-cancer agent, etc.), or at any administration schedule established by a healthcare professional.
- the effectiveness of cancer therapy is typically measured in terms of “response.”
- the techniques to monitor responses can be similar to the tests used to diagnose cancer such as, but not limited to:
- test used whether blood test, cell count, or tumor marker test, it is repeated at specific intervals so that the results can be compared to earlier tests of the same type.
- the tumor burden of a treated patient is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or any other range bound by these values.
- the 1-year survival rate of treated individual is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or any other range bound by these values.
- the 5-year survival rate of treated individual is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or any other range bound by these values.
- the 10-year survival rate of treated individual is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or any other range bound by these values.
- the subject has a sustained remission of at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 22 months, at least 24 months, at least 27 months, at least 30 months, at least 33 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, or at least 60 months or more.
- the term “substantially free of cancer” refers to a subject which does not have clinical evidence of cancer or cancer cells, or cancer stem cells.
- the method may help to treat or alleviate conditions, symptoms, or disorders related to cancer.
- these conditions or symptoms may include, but are not limited to, anemia, asthenia, cachexia, Cushing’s Syndrome, fatigue, gout, gum disease, hematuria, hypercalcemia, hypothyroidism, internal bleeding, hair loss, mesothelioma, nausea, night sweats, neutropenia, paraneoplastic syndromes, pleuritis, polymyalgia rheumatica, rhabdomyolysis, stress, swollen lymph nodes, thrombocytopenia, Vitamin D deficiency, or weight loss.
- the administration of the RAR ⁇ selective agonist prolongs the survival of the individual being treated.
- Example 1 The Bone Marrow Niche Induces a Bortezomib Resistance in Multiple Myeloma
- MM Multiple myeloma
- PCs malignant plasma cells
- Ig monoclonal immunoglobulin
- Novel therapies including proteasome inhibitors, have significantly extended the survival of patients with MM but have failed to achieve a cure.
- Increasing evidence demonstrates that interactions with the BM microenvironment play a critical role in the survival of MM cells during chemotherapy.
- the mechanisms mediating this BM niche-dependent chemoprotection are incompletely understood and remain a critical area of research.
- CD138+ MM cells that resemble mature B cells and are resistant to bortezomib (BTZ). Like their normal B cell counterparts, these CD138- MM cells are capable of clonogenic growth and differentiation into CD138+ PCs. Moreover, these cells are enriched during minimal residual disease (MRD), suggesting a critical role in disease relapse. Differential BTZ sensitivity of CD138+ and CD138- MM cells may be explained by their secretory activity. As a result of their abundant Ig production, CD138+ PCs are highly dependent on an intact proteasome pathway to degrade improperly folded proteins.
- MM cells Primary MM cells were obtained from patients with newly diagnosed or relapsed MM under an IRB-approved protocol at The Johns Hopkins University. Briefly, mononuclear cells were isolated from fresh BM aspirates by density gradient centrifugation (Ficoll-Paque); CD138+ cells were then selected via magnetic beads and columns and incubated in RPMI 1640, 10% FCS, L-glutamine, and P/S at 37° C.
- BM stromal cells Primary human BM stromal cells were derived from aspirates collected from healthy donors under an IRB-approved protocol at Johns Hopkins. Briefly, total mononuclear cells isolated from BM aspirates were cultured in Iscove’s modified Dulbecco’s medium (IMDM) supplemented with 10% horse serum, 10% FCS, 10-5 M hydrocortisone 21-hemisuccinate, P/S, and 0.1 mM ⁇ -mercaptoethanol ( ⁇ -ME) (FBMD1 media). The following day, cells in suspension were removed by washing twice with PBS, and the media were replaced. Attached stromal cells were incubated at 33° C. until a confluent monolayer was obtained. Mouse primary BM stromal cells were isolated following the same protocol, after isolation of total BM mononuclear cells from mouse femurs.
- IMDM modified Dulbecco’s medium
- FBMD1 media 0.1 mM ⁇ -mercaptoethanol
- BM stromal cells were derived from Smo fl/fl mice and transduced with the retroviral vector PIG-Cre encoding Cre-recombinase (Addgene; catalog 50935) or a control vector (Addgene; catalog 18751), respectively.
- Successfully infected cells were selected using 4 ⁇ g/ml puromycin for 5 days and confirmed by expression of GFP via flow cytometry.
- the pLenti-CMV-LUC-Puro lentiviral vector (plasmid 17477) was used to generate H929 Luc+ cells.
- Cyp26a1 cDNA (Origene) was amplified via PCR using primers incorporating the restriction sites BamHI and EcoRI and cloned into the pCR2.1 vector. Cyp26a1 cDNA was confirmed via Sanger sequencing, and the fragment was isolated after digestion with the restriction enzymes BamHI and EcoRI and subcloned into the corresponding sites of the pBABE vector. Lentiviral particles were produced as previously described. Successfully infected stromal cells were selected using 3 ⁇ g/ml G-418 for 10 days, and expression of Cyp26a1 was confirmed by qRT-PCR.
- Transwell experiments For Transwell experiments, 6-well plates were coated with 0.1% gelatin in PBS for 30 min at 37° C. The gelatin solution was removed, and the stromal cells were cultured overnight in FBMD1 media at a density of 10 ⁇ 10 4 cells/well in 2 ml of media to obtain a confluent monolayer. At that time, Transwell inserts (Corning) were placed over the stroma cultures, and MM cell lines (1 ⁇ 10 6 in 1 ml) were seeded in the Transwell for 24 hr at 37° C. Following this incubation, Transwell and MM cells were removed, and stromal cells were detached from the wells and analyzed by qRT-PCR for CYP26 expression.
- MM cells were separated from BM stromal cells by gently pipetting several times around the well. Detached cells were centrifuged, resuspended in fresh media, and incubated in a 24-well plate for 1 hr at 37° C. During this short incubation period, contaminating stromal cells attached to the well, while MM cells remained in suspension. MM cells were then recovered by gently pipetting. This protocol was used for qRT-PCR and CFU coculture experiments. The purity achieved using this protocol was confirmed by flow cytometry to be 98%-99% MM cells and less than 2% contaminating stroma.
- Clonogenic assays After treatment, MM cells were collected, washed with PBS, and plated at a density of 5,000 cells/ml in 1 ml of 1.32% methylcellulose supplemented with 30% FBS, 10% BSA, L-glutamine, P/S, and 0.1 mM ⁇ -ME. Cells were plated in triplicate in 35-mm culture dishes, incubated at 37° C., and scored for the presence of colonies 14 days later.
- MM cells were collected, washed with PBS, and stained for 15 min at room temperature with phycoerythrin-conjugated (PE-conjugated) anti-CD138. Cells were washed to remove unbound antibody and evaluated in a FACSCalibur system (BD Biosciences). Stromal cells were identified by GFP expression, and viable cells were identified using 7-aminoactinomycin D (7-AAD). To calculate cell numbers, live GFP- cells were normalized to calibration beads.
- PE-conjugated phycoerythrin-conjugated
- Mouse xenografts 1 ⁇ 10 6 H929 Luc+ cells and 1 ⁇ 10 6 mouse BM stromal cells were resuspended in 100 ⁇ l Matrigel, diluted with RPMI (1:1), and injected subcutaneously into 16-week-old male NSG mice. After 4 days, treatment with BTZ (0.5 mg/kg i.p. twice weekly) and IRX (10 mg/kg i.p. daily) was initiated. Tumor burden was assessed by bioluminescence using the In Vivo Imaging System (PerkinElmer). For imaging, mice were exposed to 120 mg/kg D-luciferin via intraperitoneal injection 10-5 min before imaging and were anesthetized using isoflurane. Images were analyzed with Living Image Software, version 2.5 (PerkinElmer), and data were quantified as photons/second.
- mice For the systemic MM model, 2 ⁇ 10 6 Luc+/GFP+ H929 cells were injected via the tail vein into 16-week-old male NSG mice. After engraftment, as determined by an exponential increase in bioluminescence, mice were treated with BTZ (0.5 mg/kg i.p.) twice weekly and with IRX (10 mg/kg) once daily. Tumor burden was assessed by bioluminescence, as above.
- the BM niche limits PC differentiation by modulating retinoid signaling.
- a population of MM progenitors, phenotypically similar to B cells, is intrinsically resistant to BTZ and contributes to MRD and relapse.
- the BM niche plays a role in determining the phenotype of MM cells, the mRNA expression of B cell and PC markers in MM H929 cell lines ( FIGS. 1 A-D ) and MM CD138+ primary cells ( FIGS. 1 E-H ) was analyzed following coculture with mouse BM stroma using human-specific primers.
- B cell lymphoma 6 (BCL6), a transcriptional repressor that promotes self-renewal of germinal center B cells and prevents PC differentiation, was upregulated in the presence of BM stromal cells ( FIGS. 1 A, 1 E ).
- BCL6 B lymphocyte-induced maturation protein 1
- XBP1s spliced X box-binding protein 1
- FIGS. 1 B, C, F, G C/EBP homologous protein
- C/EBP homologous protein (CHOP), a key component of the UPR pathway, was downregulated in the presence of BM stromal cells ( FIGS. 1 D, H ).
- CYP26 enzymes were highly expressed in BM mesenchymal cells, while their expression was barely detectable in MM cells. Since retinoid signaling promotes PC differentiation and potentiates Ig secretion, it was determined whether stromal CYP26 is responsible for inducing a B cell phenotype in MM cells. To this end, coculture conditions were treated with the CYP26 inhibitor R115866 (R115) or the CYP26-resistant RA receptor ⁇ -selective (RAR ⁇ -selective) retinoid IRX5183 (IRX).
- CD138 is a hallmark of normal PC differentiation as well MM PCs. Consistent with mRNA levels of PC markers, surface CD138 expression was markedly decreased by coculture with BM stromal cells or incubation with AGN. Incubation of BM stromal cell cocultures with R115 or IRX restored CD138 expression in MM cells. R115 did not significantly affect the expression of differentiation markers in liquid conditions by quantitative reverse transcription-PCR (qRT-PCR) or flow cytometry, while IRX induced comparable changes, irrespective of the presence or absence of BM stroma. Taken together, these data suggest that retinoid signaling promotes PC differentiation of MM cells and that this process is blocked by stromal CYP26-mediated metabolism of RA.
- qRT-PCR quantitative reverse transcription-PCR
- flow cytometry flow cytometry
- a RA-low microenvironment induces BTZ resistance.
- MM cell lines and MM CD138+ primary cells were incubated with BM stroma for 5 days, followed by BTZ treatment.
- BM stroma liquid
- MM cells were highly sensitive to BTZ ( FIGS. 2 A-B ).
- incubation with BM stroma induced BTZ resistance, which was overcome by CYP26 inhibition via R115 or by the CYP26-resistant retinoid IRX.
- treatment of MM cells with the pan-RAR antagonist AGN mimicked the changes induced by BM stromal cells ( FIG. 3 ), decreasing BTZ sensitivity.
- MM xenograft was developed by injecting 2 ⁇ 10 6 H929 luciferase+ (Luc+) cells via the tail vein of nonobese, diabetic, severe combined immunodeficiency IL-2 receptor ⁇ -KO (NSG) mice.
- the animals were randomized to receive IRX, BTZ, or a combination of both, and disease burden was followed weekly by bioluminescence imaging ( FIG. 4 ).
- Mice treated with BTZ showed decreased tumor growth compared with untreated controls; however, some MM cells remained resistant to BTZ, as demonstrated by the continued increase in bioluminescence.
- mice treated with IRX monotherapy showed a decrease in tumor burden compared with untreated mice.
- MM cells induce stromal CYP26.
- Recent studies have demonstrated the existence of a bi-directional crosstalk, in which not only stromal cells provide a protective microenvironment, but also cancer cells actively adapt and build a reinforced niche. Thus, it was determined whether MM cells reinforce a protective microenvironment by strengthening the ability of BM stroma to inactivate retinoids.
- Stromal CYP26 expression was analyzed by qRT-PCR in BM mesenchymal cells following a 24-hr coculture with MM cells.
- the isoenzyme CYP26A1 was highly upregulated by all 3 MM cell lines tested ( FIGS. 5 A-C ). In contrast, the isoenzyme CYP26B1 showed little to no changes in mRNA levels.
- Conditioned media derived from MM cells also upregulated CYP26A1 in BM stromal cells, although to a lesser extent. This could be explained by the presence of physical interactions in coculture experiments, or the lack of continuous production of soluble ligands by MM cells in conditioned media experiments. Consistent with the latter, stromal CYP26A1 was highly upregulated when MM and BM stromal cells were separated by a Transwell that prevented physical contact but allowed the diffusion of soluble factors ( FIGS. 5 A-C ).
- MM cells produce a variety of soluble factors including cytokines (IL-1, IL-3, IL-6, TNF- ⁇ ) as well as Hedgehog ligands such as sonic hedgehog (SHH), which could impact the BM stromal compartment. Therefore, it was determined whether any of these factors was responsible for the observed upregulation of CYP26A1 on BM stromal cells. Of the soluble factors tested, only SHH produced a sustained overexpression of CYP26A1, while IL-1, IL-3, IL-6, and TNF- ⁇ had no significant effects.
- cytokines IL-1, IL-3, IL-6, TNF- ⁇
- SHH sonic hedgehog
- SHH is expressed by BM stromal cells and thus may be able to activate the Hedgehog pathway in an autocrine manner
- its expression was considerably higher in MM cells compared with that detected in BM stroma, suggesting that paracrine activation may play a dominant role.
- PTCH1 protein patched homolog 1
- activation of stromal Hedgehog significantly correlated with CYP26A1 upregulation.
- MM1S cells with the highest expression of SHH also induced the highest expression of both PTCH1 and CY26A1 in stromal cells.
- SHH has a half-life of less than 1 hr, which may explain the reduced effect of MM-conditioned media on stromal CYP26A1 expression compared with that observed in coculture and Transwell experiments.
- BM mesenchymal cells derived from Smo fl/fl mice were transduced with a retroviral vector encoding Cre recombinase (Smo-KO stroma).
- Mouse Smo fl/fl stromal cells transduced with an empty retroviral vector were used as a control (WT stroma).
- the transduced BM stromal cells were cocultured with MM cells for 24 hr.
- Smo-KO stroma had a decreased ability to upregulate Cyp26a1 in response to MM cells compared with WT stroma ( FIGS. 6 A-C ).
- SMO inhibitor cyclopamine partially overcame stromal Cyp26a1 upregulation by MM cells.
- Paracrine Hedgehog produced by MM cells reinforces a protective microenvironment. Given the observations that stromal CYP26 activity may be responsible for BTZ resistance in MM cells, it was assessed whether paracrine Hedgehog secreted by MM cells reinforces a chemoprotective niche by regulating retinoid metabolism. It was first investigated whether modulation of Hedgehog signaling paralleled the retinoid-dependent phenotypes observed previously. Disruption of paracrine Hedgehog signaling in Smo-KO stroma cocultures partially restored PC differentiation (downregulation of BCL6 and upregulation of BLIMP1, XBP1, and CHOP) in H929 ( FIGS. 9 A-D ) and primary CD138+ MM cells ( FIGS.
- Cyp26a1 expression in Smo-KO stroma was rescued via lentivirus-mediated gene transfer (pBABE-Cyp26a1) in order to achieve comparable CYP26A1 levels in WT (WT-Cyp26a1) and Smo-KO (Smo-KO-Cyp26a1) stromal cells. If the role of paracrine Hedgehog was independent of retinoid signaling, the relative inability of Smo-KO stroma to induce a B cell phenotype and BTZ resistance should have persisted even after Cyp26a1 upregulation.
- Cyp26a1 overexpression rescued the ability of Smo-KO stroma to induce a B cell phenotype and restored the expression of differentiation markers and BTZ resistance to levels comparable to those detected in WT and WT-Cyp26a1 stroma coculture conditions. This finding is consistent with the hypothesis that paracrine Hedgehog reinforces a protective niche via Cyp26a1 upregulation.
- a xenograft model of MM-niche interactions was developed.
- Each mouse carried 2 subcutaneous tumors consisting of H929 Luc+ cells and either WT (anterior tumors) or Smo-KO stroma (posterior tumors). Mice were treated with IRX (10 mg/kg i.p. daily), BTZ (0.5 mg/kg i.p. twice weekly), or a combination of both.
- IRX 10 mg/kg i.p. daily
- BTZ 0.5 mg/kg i.p. twice weekly
- the growth of tumors bearing WT or Smo-KO stroma was not different in untreated or IRX-treated groups ( FIGS. 7 and 8 ).
- retinoids as differentiation therapy has proved beneficial only in patients with acute promyelocytic leukemia (APL).
- APL acute promyelocytic leukemia
- CYP26 expression by BM stromal cells may explain the lack of a clinical benefit of natural retinoids, despite their in vitro activity.
- Recent studies have highlighted the efficacy of CYP-resistant synthetic retinoids in differentiating cancer cells and sensitizing them to targeted therapy. For instance, AM80 differentiates FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) acute myeloid leukemia (AML) cells and increase their sensitivity to FLT3 inhibitors.
- FLT3/ITD FMS-like tyrosine kinase 3/internal tandem duplication
- AML acute myeloid leukemia
- synthetic retinoids reverse a stem cell phenotype in BCR-ABL1+ leukemic lymphoblasts and substantially increase their responsiveness to tyrosine kinase inhibitor (TKI) therapy in vivo.
- TKI tyrosine kinase inhibitor
- MM cells utilize physical contacts to maintain drug resistance and survive within the BM niche.
- therapeutic strategies to overcome stromal chemoprotection have focused on mobilization of malignant cells from the BM niche by targeting adhesion molecules or chemokines such as CXCR4.
- MM cells exposed to a retinoid-low microenvironment acquire a BTZ-resistant phenotype that is maintained even after these cells are displaced from their niche.
- Initial clinical studies have shown improved response rates in relapse/refractory patients receiving the CXCR4 inhibitor plerixafor in combination with BTZ; however, this data suggest that such mobilization approaches may be insufficient to eliminate MM B cells.
- CYP26 upregulation is associated with an “activated stromal subtype” and a significantly worse prognosis in patients with pancreatic cancer, a disease in which paracrine Hedgehog signaling is well established.
- the extent to which Hedgehog ligands produced by cancer cells contribute to this “activated” stromal phenotype and high CYP26 levels is unknown.
- BM mesenchymal cells migrate and become a relevant cell population in the stromal compartment of these tumors.
- the endosteal region is the primary niche of MM, AML, and micrometastatic disease from solid tumors. Within the osteoblastic region, these cancer cells maintain a quiescent, stem cell phenotype and are protected from chemotherapy-induced apoptosis. It is likely that these cancer cells rely on the same cues from the BM microenvironment as normal hematopoietic stem cells do to survive chemotherapy and perpetuate the disease.
- the BM microenvironment protected MM and AML cells by directly inactivating various chemotherapy agents via expression of CYP3A4 and other detoxifying enzymes.
- Another potential mechanism of microenvironment-mediated drug resistance is now demonstrated: creation of a retinoid-low niche that maintains a drug-resistant B cell phenotype.
- a CYP26-resistant retinoid potentiated the activity of BTZ against MM in the BM niche provides a therapeutic opportunity to bypass this mechanism of resistance.
- the BM stroma which expresses inducibly high levels of CYP26, metabolically inactivates ATRA and provides a protected environment for AML cancer stem cells.
- Synthetic, CYP26-resistant RAR ⁇ agonists, such as IRX5183 and AM80 should be able to bypass stroma-mediated protection of AML cells and differentiate the cancer stem cells resident in the protected environment of bone marrow niche.
- clonogenic growth experiments were conducted in the non-APL AML cell lines OCI-AML 3 and Kasumi-1 and APL NB4 cells, which were treated with ATRA, IRX5183, and AM80 in the presence or absence of stroma.
- ATRA inhibited clonogenic growth only in the absence of stroma.
- IRX5183 inhibited clonogenic growth to a similar extent in the presence or absence of stroma ( FIGS. 10 A-C ).
- AM80 also inhibited clonogenic growth in the presence of stroma but not as effectively as IRX5183.
- AML Acute myeloid leukemia
- ATRA all-trans retinoic acid
- RA retinoic acid
- APL acute promyelocytic leukemia
- ATRA was considered an attractive therapeutic strategy for other AML subtypes.
- APL, and most non-APL AMLs undergo terminal differentiation and are therefore successfully treated by ATRA in vitro.
- ATRA has not proven effective in non-APL AMLs in clinical trials.
- Retinoic acid plays a significant role in the differentiation of hematopoietic stem cells (HSCs).
- HSCs hematopoietic stem cells
- CYP26 cytochrome P450 enzyme
- BM bone marrow
- Several AML cell lines, both APL and non-APL, are sensitive to RA-induced differentiation, but this effect was abrogated in the presence of BM stroma. Thus, it may be useful to treat AML with a retinoid that is resistant to metabolism by the CYP26 pathway.
- IRX5183 is a RAR ⁇ selective agonist which is resistant to CYP26 metabolism.
- IRX5183 Use of IRX5183 in AML provides a novel targeted approach to this disease, which has the potential to change the prognosis of this and other hematologic malignancies.
- HR-MDS high risk myelodysplastic syndrome
- Eligibility criteria - dose expansion This phase will recruit patients with relapsed/refractory AML (cohort 1) and patients with HR-MDS not responding to hypomethylating agents (cohort 2) and will follow the noted eligibility criteria above (aside from #5 above in MDS patients), including pathologically confirmed CMML or MDS with high risk features at the time of referral as defined by:
- HR-MDS patients are required to have failed or relapsed after an initial response to hypomethylating agents or have refused to receive hypomethylating therapy. Failure to respond is defined as failing to achieve a CR, PR or HI after at least 4 cycles of hypomethylating therapy.
- IRX5183 is administered orally in daily doses continually in 28 day cycles until toxicity or disease progression. Bone marrow testing during each of the first 4 cycles determines marrow status and response. Only patients with relapsed or refractory AML are enrolled in the dose escalation phase.
- the starting dose (DL1) of single agent IRX5183 is 30 mg/m 2 /day, and the individual dosing levels are noted below:
- Dose level (DL) Daily dose (mg/m 2 ) DL(-1) 15 DL1 30 DL2 45 DL3 60 DL4 75
- the phase-expansion part of the study uses the optimal dose identified in the phase-escalation part of the study and includes two separate arms; one for AML patients and another for HR-MDS, and each of these two arms will recruit 26 patients.
- Dose levels are explored according to a traditional 3+3 design, with an aim to enroll 3 subjects at a time to determine the toxicity profile of IRX5183 in AML patients. If none of the three patients receiving DL1 experiences a DLT, another three patients will be treated at the next higher dose level. However, if one of the first three patients experiences a DLT, three more patients will be treated at the same dose level. The dose escalation will continue until at least two patients among a cohort of 3-6 patients experience DLTs. If two or more patients experience DLT on DL1, the next patient will be recruited to DL(-1). The MTD of single agent IRX5183 will be the highest dose at which 0 or 1 DLT are seen in a cohort of six subjects.
- phase 2 dose expansion cohort patients with AML are continued to be enrolled at the MTD, with goal of enrolling 26 patients (inclusive of patients treated at the MTD in first phase of the trial). Patients continue on single agent IRX5183 until they experience toxicity or disease progression. If patients achieve a complete remission, they have the option to consolidate with transplant, chemotherapy, and/or continue on maintenance IRX5183. If patients achieve a partial response or hematologic improvement they have the option to obtain salvage therapy in combination with IRX5183. For MDS patients, the phase 2 dose expansion cohort will recruit 26 patients who receive single agent IRX5183 at the MTD from the first phase of the trial. They also continue until undue toxicity or disease progression. Patients who achieve hematologic improvement or better have the option to consolidate with transplant, combine with demethylating agent therapy, or continue on maintenance IRX5183.
- Plasma concentrations of IRX5183 are evaluated for the escalation and expansion phases, targeting safe and effective retinoid levels by pharmacokinetics using LCM-MS (liquid chromatography-mass spectroscopy tandem). Targeting peak levels of 1 pM should avoid systemic toxicity, while presumably preserving local BM niche retinoid levels.
- the plasma concentration of IRX5183 are obtained using a single 2 mL blood sample, pre-dose on day 14. Samples are shipped to and analyzed by the designated analytical laboratory.
- BM cellular (normal HSCs and LSCs) concentrations, peripheral blood and bone marrow blast counts, markers of differentiation, apoptosis, and clonogenic growth are determined.
- a bone marrow aspirate and biopsy are obtained at baseline, on day 14, and at the end each of the first 4 cycles of therapy. Differentiation is assessed using flow cytometry, comparing expression of differentiation markers on CD45 positive cells and ALDHint LSCs on day 14 marrow versus baseline.
- FISH analysis is also conducted after each cycle for patients with baseline abnormalities to determine if leukemic clone still present on day 14.
- RAR ⁇ selective agonist Patients receiving RAR ⁇ selective agonist are monitored for response criteria based on hematological parameters including complete blood counts and percentage of leukemia blasts in the peripheral blood and in the bone marrow. Patients with improved neutrophil count, decreased transfusion requirements of red blood cells and platelets together with decreased percentage of blasts in the bone marrow and induction of differentiation and apoptosis of these malignant blasts are deemed responsive to therapy. Quality of life parameters such as pain, performance status and participation in activity of daily living and instrumental activities of daily living are assessed to evaluate the impact of this therapy on study patients.
- Use of this RAR ⁇ selective agonist is expected to improve hematological and quality of life parameters in patients with MDS/AML and solid malignancies.
- the use of the RAR ⁇ agonist which is CYP26 resistant may result in differentiation and thus elimination of minimal residual disease in the bone marrow of these patients.
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
- This application is a divisional of U.S. Pat.
Application 17/136,428, filed Dec. 29, 2020, which is a divisional of U.S. Pat.Application 15/777,868, filed May 21, 2018, now U.S. Pat. 10,940,127, which is a 35 U.S.C. 371 national phase entry of PCT/US2016/063659, filed Nov. 23, 2016, which claims the benefit of U.S. Provisional Pat. Application 62/260,098 filed Nov. 25, 2015; the entire contents of all of which are each incorporated by reference herein. - This invention was made with government support under HL127269 and CA015396 awarded by the National Institutes of Health. The government has certain rights in the invention.
- Disclosed herein are methods of treating cancer with CYP26-resistant retinoic acid receptor alpha (RARα) selective agonists.
- Normal hematopoietic stem cells (HSCs) are primed to be highly sensitive to retinoids but are maintained in a retinoid signaling-naïve state by isolating them from physiologic levels of retinoids. The bone marrow microenvironment, by expression of the enzyme CYP26 metabolically inactivates retinoic acid, regulates the exposure of the bone marrow to retinoids. This mechanism (CPY26-mediated retinoid metabolism) is dynamic and used by the bone marrow stroma to match HSC behavior to physiological needs. For example, steady state low levels of retinoids in the bone marrow niche maintains HSCs in a quiescent state, while during situations of stress (i.e., exposure to radiation or chemotherapy) higher retinoid levels are maintained to recruit HSCs into cell division and rescue hematopoiesis.
- In subjects with hematologic malignancies, cancer HSCs are protected from retinoids by stromal CYP26, in a similar fashion to the normal situation. However, because of other alterations in the bone marrow niche in hematologic malignancies, such as differences in aldehyde dehydrogenase (ALDH) activity, there exists a therapeutic window for retinoids to be useful in the treatment of hematologic malignancies. Expression of CYP26 by the bone marrow microenvironment contributes to the protection of immature acute myeloid leukemia (AML) cells from all-trans retinoic acid (ATRA) and may explain why ATRA is not effective in treating AML. Exposure to pharmacological concentrations of ATRA acting through retinoic acid receptor gamma (RARy), induces CYP26 expression in the bone marrow microenvironment, thus protecting the cancer stem cells therein from retinoid activity. However, the use of retinoid analogs which are not inactivated by CYP26 enables such retinoids to terminally differentiate and thus eliminate the cancer HSCs from the protective bone marrow niche. Since such differentiation is mediated by RARα, and the use of RARα specific analogs, which are CYP26 resistant, enables the therapeutic differentiation-inducing activity without inactivation by the CYP26 enzyme.
- Disclosed herein are methods of treating cancer with CYP26-resistant, retinoic acid receptor (RAR) alpha (RARα) selective agonists and their use in the treatment of malignancies by acting upon cancer stem cells resident in the bone marrow.
- Thus, provided herein are methods for treating a hematologic malignancy comprising administering to a subject in need thereof an effective dose of a CYP26-resistant RARα selective agonist, whereby as a result of the treatment the tumor burden is reduced in the subject.
- In some embodiments, administration of an effective dose of the CYP26-resistant RARα selective agonist results in the elimination of minimal residual disease or cancer stem cells from the bone marrow niche of the subject, thereby rendering the subject substantially free of cancer. In certain embodiments, administration of an effective dose of the CYP26-resistant RARα selective agonist results in sensitization of minimal residual disease to other anticancer agents, whereby combination of the CYP26-resistant RARα selective agonist with other anticancer agents results in elimination of minimal residual disease or cancer stem cells from the bone marrow niche of the subject, thereby rendering the subject substantially free of cancer.
- In certain embodiments, the cancer stem cell is a hematologic cancer stem cell (HSC). In some embodiments, the hematologic malignancy is acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), accelerated CML, CML blast phase (CML-BP), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin’s disease (HD), non-Hodgkin’s lymphoma (NHL), follicular lymphoma, mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma (MM), Waldenstrom’s macroglobulinemia, a myelodysplastic syndrome (MDS), refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), or a myeloproliferative syndrome.
- In certain embodiments, the CYP26-resistant RARα selective agonist is
- In other embodiments, the CYP26-resistant RARα selective agonist is tamibarotene (AM80), AM580, or
Re 80. - In some embodiments, as a result of the administration, the subject remains in remission longer than 5 years.
- Also disclosed herein are methods for treating a solid tumor malignancy comprising administering to a subject in need thereof an effective dose of a CYP26-resistant RARα selective agonist, and at least one additional anti-cancer agent, whereby as a result of the treatment, the tumor burden is reduced in the subject.
- In certain embodiments, administration of an effective dose of a RARα agonist which is not metabolized by CYP26 results in the elimination of minimal residual disease or cancer stem cells in the bone marrow niche of the subject, thereby rendering the subject substantially free of cancer.
- In some embodiments, the solid tumor malignancy is a type of cancer which typically metastasizes to the bone marrow. In some embodiments, the additional anti-cancer agent is an agent listed in Table 1. In certain embodiments, the solid tumor malignancy is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, brain cancer, bone cancer, or soft tissue sarcoma.
- In some embodiments, the additional anti-cancer agent is selected from the combinations in Table 1. In certain embodiments, the additional anti-cancer agent is trastuzumab, tamoxifen, anastrazole, exemestrane, letrozole, crizotinib, aberatrone, enzalutamide, bicalutemide, bortezomib, or thalidomide.
- In some embodiments, as a result of the administration, the subject remains in remission longer than 1 year, longer than 2 years, longer than 3 years, longer than 4 years, or longer than 5 years.
- In some embodiments, as a result of the administration, the subject remains in remission for at least 1 year (e.g., 1-2 years, 1-3 years, 1-4 years, 1-5 years, 2-3 years, 2-4 years, 2-5 years, 3-4 years, 3-5 years, or 4-5 years).
- In some embodiments, as a result of the administration, the subject remains in remission for 1-2 years, 1-3 years, 1-4 years, or 1-5 years.
- Also disclosed herein are methods for treating cancer, comprising administering to a subject in need thereof a CYP26-resistant retinoic acid receptor alpha (RARα) selective agonist and bortezomib.
- Also disclosed herein are methods for treating cancer, comprising administering to a subject in need thereof an effective dose of a CYP26-resistant retinoic acid receptor alpha (RARα) selective agonist and bortezomib.
- Also disclosed herein are methods for treating cancer, comprising administering to a subject in need thereof an effective dose of a CYP26-resistant retinoic acid receptor alpha (RARα) selective agonist and bortezomib, whereby as a result of the treatment the tumor burden is reduced in the subject.
- Also disclosed herein are methods for treating multiple myeloma comprising administering to a subject in need thereof an effective dose of a CYP26-resistant retinoic acid receptor alpha (RARα) selective agonist and bortezomib, whereby as a result of the treatment the tumor burden is reduced in the subject.
- Also disclosed herein are methods for treating multiple myeloma comprising administering to a subject in need thereof an effective dose of a IRX5183 and bortezomib, whereby as a result of the treatment the tumor burden is reduced in the subject.
- Also disclosed herein are methods for treating cancer, comprising administering to a subject in need thereof IRX5183 and bortezomib.
- Also disclosed herein are methods for treating cancer, comprising administering to a subject in need thereof an effective dose of a IRX5183 and bortezomib.
- Also disclosed herein are methods for treating cancer, comprising administering to a subject in need thereof an effective dose of a IRX5183 and bortezomib, whereby as a result of the treatment the tumor burden is reduced in the subject.
-
FIGS. 1A-H depicts the relative concentration of plasma markers BCL6 (FIGS. 1A and E ), BLIMP-1 (FIGS. 1B and F ), XBPS-1 (FIGS. 1C and G ), and CHOP (FIGS. 1D and H ) and in multiple myeloma (MM) cell lines H929 (FIGS. 1A-D ) or CD138+ MM cells from three different patient samples (FIGS. 1E-H ) incubated for 5 days either in the absence of stroma (Liquid), with or without AGN (RA receptor antagonist AGN194310, 1 µM), or cocultured with BM mesenchymal cells (Stroma), with or without R115 (CYP26 inhibitor R115866, 1 µM) or IRX (CYP26-resistant retinoid IRX5183, 1 µM). Expression in untreated liquid conditions was set at 1. Data are representative of 3 independent experiments with similar results and represent the mean ± SEM. *P ≤ 0.05 and **P ≤ 0.01, by repeated-measures 1-way ANOVA for determination of statistical significance between groups; P values were corrected for multiple comparisons using Dunnett’s test. Ctrl, control; max, maximum. -
FIGS. 2A-B depicts the clonogenic recovery (CFU) of H929 cells (FIG. 2A ) or cellular recovery of primary CD138+ MM cells from 3 different patient samples (FIG. 2B ). MM cells were treated with BTZ (2.5 nM) for 48 hours after being incubated for 5 days either in the absence of stroma (Liquid), with or without the pan-RAR inhibitor AGN (1 µM), or in the presence of BM mesenchymal cells (Stroma), with or without the CYP26 inhibitor R115 (1 µM) or the CYP26-resistant retinoid IRX (1 µM). Clonogenic or cellular recovery was normalized to each condition in the absence of BTZ. -
FIG. 3 depicts clonogenic recovery of H929 cells treated with BTZ (2.5 nM). MM cells were incubated for 5 days in the absence (Liquid) or presence of BM mesenchymal cells (Stroma), with or without R115 (1 µM). Following this preincubation, H929 cells were separated from BM stroma, cultured in fresh media for 0 to 48 hours, and then treated with BTZ (2.5 nM) for 48 hours. Clonogenic recovery was normalized to each condition in the absence of BTZ. -
FIG. 4 depicts bioluminescent images of systemic MM xenografts. Following engraftment of H929 Luc+ cells, mice were treated with IRX (n = 4), BTZ (n = 5), or a combination of both (n = 5) for 4 weeks. Data represent the mean ± SEM of the fold change in bioluminescence (photons/second) fromday 0. -
FIGS. 5A-C depicts the effects of MM cells on the expression of CYP26A1 in BM stroma. Relative quantification of CYP26A1 mRNA in human BM mesenchymal cells incubated for 24 hours either in the absence (Ctrl) or presence (Coculture or Transwell) of MM cells (H929 [FIG. 5A ], MM1s [FIG. 5B ], U266 [FIG. 5C ]). Expression in untreated BM stroma (Ctrl) was arbitrarily set at 1. -
FIGS. 6A-C depicts the relative quantification of CYP26A1 mRNA in mouse wild type (WT) or Smo-KO BM stroma incubated for 24 hr in the absence (Ctrl) or presence (Coculture or Transwell) of MM cells (H292, MM1s, U266). Expression in untreated WT or Smo-KO stroma was arbitrarily set at 1 for the respective treated conditions. Data represent the mean ± SEM of 3 independent experiments. *P ≤ 0.05 and **P ≤ 0.01, by unpaired, 2-tailed Student’s t test. -
FIG. 7 depicts bioluminescent images of mice showing tumor burden during 4 weeks of treatment with IRX (10 mg/kg), BTZ (0.5 mg/kg), or the combination. Anterior tumors consisted of a combination of MM1S luciferase+ cells and SmoFI/FI BM stroma cells transduced with a control vector (WT BM stroma). Posterior tumors consisted of a combination of MM1S luciferase+ cells and SmoFI/FI BM stroma cells transduced with Cre-recombinase (Smo KO BM stroma). -
FIG. 8 depicts the fold change in bioluminescence (photons/second) of tumors during 4 weeks of treatment. The change in bioluminescence for each tumor atday 1 was normalized to the change in bioluminescence atday 14 and at the end of treatment (day 28). -
FIGS. 9A-H depicts the relative quantification of BCL6 (B cell marker), BLIMP, XBP1s, and CHOP (PC markers) in H929 cells (FIG. 9A ) and primary CD138+ MM cells (FIG. 9B ) from 3 different patient samples incubated for 5 days either in the absence of stroma (Ctrl) or cocultured with WT or Smo-KO stromal cells. Expression in untreated liquid conditions was set at 1. Data represent the mean ± SEM. *P ≤ 0.05 and **P ≤ 0.01, by repeated-measures 1-way ANOVA to determine statistical significance between treatment groups; P values were corrected for multiple comparisons using Dunnett’s test. -
FIGS. 10A-C depicts stroma blockage of ATRA-mediated, but not AM80- or IRX5183-induced, differentiation and elimination of AML. (FIG. 10A ) CFU experiments with NB4 cells treated with 10-7 M ATRA, IRX5183, or 10-8 M AM80; (FIG. 10B ) OCI-AML3 cells and (FIG. 10C ) Kasumi-1 cells treated with 10-6 M ATRA, IRX5183, or 10-7 M AM80 showed a decrease in clonogenic growth compared to control with AM80 and IRX5183 both off and on stroma. Data across three independent experiments. - Disclosed herein are methods of treating cancer with CYP26-resistant, retinoic acid receptor (RAR) alpha (RARα) selective agonists and their use in the treatment of malignancies by acting upon cancer stem cells resident in the bone marrow.
- Many, if not most, malignancies arise from a rare population of cells that exclusively maintain the ability to self-renew and sustain the tumor. These cancer stem cells are often biologically distinct from the bulk of differentiated cancer cells that characterize the disease. For example, chronic myeloid leukemia (CML) occurs at the level of hematopoietic stem cells and, like their normal counterparts, CML stem cells undergo orderly differentiation. Thus, the bulk of the leukemic mass in CML consists of differentiated blood cells, whereas the rare cells responsible for disease maintenance resemble normal hematopoietic stem cells. Similarly, in multiple myeloma, which is characterized by neoplastic plasma cells, these cells appear to be terminally differentiated like their normal counterparts. The myeloma plasma cells that form the bulk of the tumor arise from a population of less differentiated cancer stem cells that resemble post-germinal center B cells. Other cancers, including but not limited to, hematological malignancies, myelodysplastic syndrome, breast cancer, prostate cancer, pancreatic cancer, colon cancer, ovarian cancer, melanoma, non-melanoma skin cancers, and brain cancers have been demonstrated to arise from corresponding cancer stem cells.
- Thus, disclosed herein are methods of treating cancer with agents which can target cancer stem cells in the protected bone marrow niche by inducing differentiation of the cancer stem cells into mature cancer cells that are susceptible to standard therapies. Administration of CYP26-resistant, RARα selective agonists which can act on the cancer stem cells in the bone marrow niche (because they are not inactivated by CYP26) is one such approach. In certain embodiments, effectiveness of therapy with a RARα selective agonist disclosed herein leads to a substantial decrease in the number of cancer stem cells in the bone marrow.
- The cancer stem cells can be enumerated by various mechanisms and reduction in their numbers as a result of administration of a CYP26-resistant RARα selective agonist measured thereby. In embodiments disclosed herein, as a result of administration of a RARα selective agonist, the cancer stem cells in the bone marrow are reduced by more than about 0.5 log, more than about 1 log, more than about 1.5 log, more than about 2.0 log, more than about 2.5 log, more than about 3.0 log, more than about 3.5 log, more than about 4.0 log, more than about 4.5 log, or more than about 5.0 log.
- Compounds with retinoid activity (vitamin A and its derivatives) have activity in cell proliferation and differentiation processes. Many biological effects of retinoids are mediated by modulating the nuclear retinoic acid receptors (RARs). The RARs activate transcription by binding to DNA sequence elements, known as RAR response elements (RARE), in the form of a heterodimer with one of the retinoid X receptors (known as RXRs). Three subtypes of human RARs have been identified and described: RARα, RARβ, and RARγ.
- As used herein, the term “RARα agonist”, is synonymous with “RARα selective agonist” and refers to a compound that selectively binds RARα. As used herein, the term “selectively binds,” when made in reference to a RARα selective agonist, refers to the discriminatory binding of a RARα selective agonist to the indicated target RARα such that the RARα selective agonist does not substantially bind with non-target receptors like a RARβ or a RARγ.
- Selective binding of a RARα selective agonist to a RARα includes binding properties such as, e.g., binding affinity and binding specificity. Binding affinity refers to the length of time a RARα selective agonist resides at its a RARα binding site, and can be viewed as the strength with which a RARα selective agonist binds its a RARα. Binding specificity is the ability of a RARα selective agonist to discriminate between a RARα and a receptor that does not contain its binding site, such as, e.g., a RARβ or a RARγ.One way to measure binding specificity is to compare the association rate of a RARα selective agonist for its RARα relative to the association rate of a RARα agonist for a receptor that does not contain its binding site; for example, comparing the association rate constant of a RARα selective agonist for its RARα relative to a RARβ and/or a RARγ.
- In some embodiments, a RARα selective agonist will have a ratio of activity at a RARα relative to a RARβ and/or a RARγ of, e.g., at least 5 times greater, at least 10 times greater, at least 15 times greater, at least 20 times greater or at least 10,000 times greater. A RAR pan agonist will have activity at a RARα, a RARβ, and a RARγ, i.e., similar potency at a RARα, a RARβ, and a RARγ.
- The binding specificity of a RARα selective agonist that selectively binds to a RARα can also be characterized as an activity ratio that such a RARα selective agonist can exert through binding to its RARα relative to a receptor not comprising its binding site, such as, e.g., a RARβ or a RARγ.In some embodiments, a RARα selective agonist that selectively binds to a RARα has an activity ratio through its RARα relative to a receptor not comprising its binding site of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 64:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least 40:1. In some embodiments, a RARα selective agonist that selectively binds to a RARα has an activity ratio through its RARα relative to a RARβ and/or a RARγ of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 64:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least 40:1. In some embodiments, a RARα selective agonist that selectively binds to a RARα has an activity ratio through its RARα relative to a receptor not comprising its binding site of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least 40:1. In some embodiments, a RARα selective agonist that selectively binds to a RARα has an activity ratio through its RARα relative to a RARβ and/or a RARγ of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least 40:1.
- RARα selective agonists useful in the methods disclosed herein are RARα selective agonists which are not metabolized by CYP26. CYP26 is a cytochrome P450 monooxygenase that metabolizes retinoic acid into inactive or less active substances which can also be readily eliminated from cells and regulates cellular levels of retinoic acid. RARα selective agonists that are readily metabolized by CYP26 are not within the scope of the present methods.
- In an aspect of this embodiment, a CYP26-resistant RARα selective agonist is a compound having the structure of formula I,
- wherein R1 is H or C1-6 alkyl;
- R2 and R3 are independently H or F; and
- R4 is a halogen.
- In some embodiments of formula I, halogen is F, Cl, Br or I. In some embodiments, of formula I, halogen is F. In some embodiments, of formula I, halogen is Cl. In some embodiments, of formula I, halogen is Br. In some embodiments, of formula I, halogen is I.
- In an aspect of this embodiment, a CYP26-resistant RARα selective agonist is a compound having a structure of formula II
- wherein R1 is H or C1-6 alkyl.
- In another aspect of this embodiment, a CYP26-resistant RARα selective agonist is the compound having the structure of formula III
- In another embodiment, a CYP26-resistant RARα selective agonist is tamibarotene (AM80; 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid). In another embodiment, a CYP26-resistant RARα selective agonist is AM580 (4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid). In another embodiment, a CYP26-resistant RARα selective agonist is Re 80 (4-[1-hydroxy-3-oxo-3-(5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid).
- As used herein, the term “CYP26-resistant” refers to RARα selective agonists which are not metabolized, degraded, or otherwise inactivated by the CYP26 enzyme and have activity within the bone marrow.
- Assays by which a compound can be tested and established whether or not it is an RARα selective agonist are described in numerous prior art publications and patents. For example, a chimeric receptor transactivation assay which tests for agonist-like activity in the RARα, RARβ, RARγ, RXRα receptor subtypes, is described in detail in US Pat. 5,455,265, which is hereby incorporated by reference for all it discloses regarding receptor transactivation assays.
- The compounds and pharmaceutical compositions disclosed herein are particularly useful for the treatment of cancer. As used herein, the term “cancer” refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term “cancer” includes, but is not limited to, solid tumors and hematologic tumors. The term “cancer” encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The term “cancer” further encompasses primary and metastatic cancers. Included within the term “cancer” are cancer stem cells.
- In certain embodiments, the cancer is a hematologic malignancy. Non-limiting examples of hematologic malignancy include acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), including accelerated CML and CML blast phase (CML-BP), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin’s disease (HD), non-Hodgkin’s lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma (MM), Waldenstrom’s macroglobulinemia, myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), (refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T), and myeloproliferative syndromes. In certain embodiments, when the cancer is a hematologic malignancy, the RARα selective agonist could be administered either as a stand-alone therapy in the absence of other anti-cancer treatments or in combination with other therapies, including but not limited to those listed below in Table 1.
- In some embodiments, the cancer is a solid tumor. In other embodiments, the cancer is a solid tumor which can metastasize to the bone. Non-limiting examples of solid tumors that can be treated by the disclosed methods include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; and soft tissue sarcoma. In certain embodiments, when the cancer is a solid tumor, the RARα selective agonist is used in combination with a cytotoxic agent or other anti-cancer agent.
- A compound disclosed herein, or a composition comprising such a compound, is generally administered to an individual as a pharmaceutical composition. Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound as disclosed herein, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, with conventional acceptable pharmaceutical excipients, and by preparation of unit dosage forms suitable for therapeutic use. As used herein, the term “pharmaceutical composition” and refers to a therapeutically effective concentration of an active compound, such as, e.g., any of the compounds disclosed herein. Preferably, the pharmaceutical composition does not produce an adverse, allergic, or other untoward or unwanted reaction when administered to an individual. A pharmaceutical composition disclosed herein is useful for medical and veterinary applications. A pharmaceutical composition may be administered to an individual alone, or in combination with other supplementary active compounds, agents, drugs or hormones. The pharmaceutical compositions may be manufactured using any of a variety of processes, including, without limitation, conventional mixing, dissolving, granulating, dragée-making, levigating, emulsifying, encapsulating, entrapping, and lyophilizing. The pharmaceutical composition can take any of a variety of forms including, without limitation, a sterile solution, suspension, emulsion, lyophilizate, tablet, pill, pellet, capsule, powder, syrup, elixir, or any other dosage form suitable for administration.
- Liquid dosage forms suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethyleneglycol (PEG), glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. In liquid formulations, a therapeutically effective amount of a compound disclosed herein typically is between about 0.0001% (w/v) to about 50% (w/v), about 0.001% (w/v) to about 10.0% (w/v), or about 0.01% (w/v) to about 1.0% (w/v).
- Solid dosage forms suitable for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
- A pharmaceutical composition disclosed herein can optionally include a pharmaceutically acceptable carrier that facilitates processing of an active compound into pharmaceutically acceptable compositions. As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio. As used herein, the term “pharmacologically acceptable carrier” is synonymous with “pharmacological carrier” and refers to any carrier that has substantially no long term or permanent detrimental effect when administered and encompasses terms such as “pharmacologically acceptable vehicle, stabilizer, diluent, additive, auxiliary, or excipient.” Such a carrier generally is mixed with an active compound or permitted to dilute or enclose the active compound and can be a solid, semi-solid, or liquid agent. It is understood that the active compounds can be soluble or can be delivered as a suspension in the desired carrier or diluent. Any of a variety of pharmaceutically acceptable carriers can be used including, without limitation, aqueous media such as, e.g., water, saline, glycine, hyaluronic acid and the like; solid carriers such as, e.g., starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient. Selection of a pharmacologically acceptable carrier can depend on the mode of administration. Except insofar as any pharmacologically acceptable carrier is incompatible with the active compound, its use in pharmaceutically acceptable compositions is contemplated. Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman’s The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003). These protocols are routine and any modifications are well within the scope of one skilled in the art and from the teaching herein.
- A pharmaceutical composition disclosed herein can optionally include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like. Various buffers and means for adjusting pH can be used to prepare a pharmaceutical composition disclosed herein, provided that the resulting preparation is pharmaceutically acceptable. Such buffers include, without limitation, acetate buffers, borate buffers, citrate buffers, phosphate buffers, neutral buffered saline, and phosphate buffered saline. It is understood that acids or bases can be used to adjust the pH of a composition as needed. Pharmaceutically acceptable antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition, such as, e.g., sodium chlorite and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor. The pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical composition useful in the claimed methods.
- “Administering”, as used herein, refers to providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering. Administration includes, but is not limited to, oral administration, nasal administration, pulmonary administration, subcutaneous administration, intravenous administration, intramuscular administration, intratumoral administration, intracavity administration, intravitreal administration, dermal administration, and transdermal administration, etc.
- Depending on the type of cancer, and the patient to be treated, as well as the route of administration, the disclosed RARα selective agonists may be administered at varying therapeutically effective doses to a patient in need thereof.
- However, the dose administered to a mammal, particularly a human, in the context of the present methods, should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
- As a non-limiting example, when administering a RARα selective agonist disclosed herein to a mammal, a therapeutically effective amount generally may be in the range of about 1 mg/m2/day to about 100 mg/m2/day. In some embodiments, an effective amount of a RARα selective agonist disclosed herein may be about 5 mg/m2/day to about 90 mg/m2/day, about 10 mg/m2/day to about 80 mg/m2/day, about 15 mg/m2/day to about 70 mg/m2/day, about 20 mg/m2/day to about 65 mg/m2/day, about 25 mg/m2/day to about 60 mg/m2/day, or about 30 mg/m2/day to about 55 mg/m2/day. In some embodiments, a therapeutically effective amount of a compound or a composition disclosed herein may be at least 10 mg/m2/day, at least 15 mg/m2/day, at least 20 mg/m2/day, at least 25 mg/m2/day, at least 30 mg/m2/day, at least 35 mg/m2/day, at least 40 mg/m2/day, at least 45 mg/m2/day, at least 50 mg/m2/day, at least 55 mg/m2/day, at least 60 mg/m2/day, at least 65 mg/m2/day,or at least 75 mg/m2/day. In some embodiments, a therapeutically effective amount of a RARα selective agonist disclosed herein may be at most 15 mg/m2/day, at most 20 mg/m2/day, at most 25 mg/m2/day, at most 30 mg/m2/day, at most 35 mg/m2/day, at most 40 mg/m2/day, at most 45 mg/m2/day, at most 50 mg/m2/day, at most 55 mg/m2/day, at most 60 mg/m2/day, at most 65 mg/m2/day, at most 70 mg/m2/day, at most 80 mg/m2/day, at most 90 mg/m2/day, or at most 100 mg/m2/day.
- Administration may be continuous or intermittent. The dosage may also be determined by the timing and frequency of administration. Thus, the RARα selective agonists disclosed herein can be given on a daily, weekly, or monthly basis for a period of time, followed by an optional drug holiday (drug free period) and that this drug administration/drug holiday cycle can be repeated as necessary.
- In certain embodiments, the RARα selective agonist is administered in combination with one or more additional anti-cancer agents. Anti-cancer agents include cytotoxic drugs, including, but not limited to, paclitaxel, docetaxel, and the like and mixtures thereof. Additional anti-cancer agents include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefmgol, chlorambucil, cirolemycin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, interleukin 2, interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-la, interferon gamma-lb, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talisomycin, tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestolone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride, and bortezomib.
- In some embodiments, the anti-cancer agent includes, but is not limited to: 5-fluorouracil, 20-epi-I,25 dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecypenol, adozelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, anti-dorsalizing morphogenetic protein-1, antiandrogen, prostatic carcinoma, antiestrogen, antineoplaston, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulacrine, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, batimastat, BCR/ABL antagonists, benzochlorins, benzoylstaurosporine, beta lactam derivatives, beta-alethine, betaclamycin B, betulinic acid, bFGF inhibitor, bicalutamide, bisantrene, bisaziridinylspermine, bisnafide, bistratene A, bizelesin, breflate, bropirimine, budotitane, buthionine sulfoximine, calcipotriol, calphostin C, camptothecin 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, collismycin 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, dexverapamil, diaziquone, didemnin B, didox, diethylnorspermine, dlhydro-5-azacytidine, 9-dioxamycin, diphenyl spiromustine, docosanol, dolasetron, doxifturidine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, epristeride, estramustine analogue, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine, fluasterone, fludarabine, fluorodaunorunicin hydrochloride, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, gallium nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide, hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridones, imiquimod, immunostimulant peptides, insulin-like growth factor-1 receptor inhibitor, interferon agonists, interferons, interleukins, iobenguane, iododoxorubicin, ipomeanol, iroplact, irsogladine, isobengazole, isohomohalicondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibiting factor, leukocyte alpha interferon, leucovorin, leuprolide+estrogen+progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogue, lipophilic disaccharide peptide, lipophilic platinum compounds, lissoclinamide 7, lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, lytic peptides, maitansine, mannostatin A, marimastat, masoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menogaril, merbarone, meterelin, methioninase, metoclopramide, MIF inhibitor, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone, mitolactol, mitomycin analogues, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofarotene, molgramostim, human chorionic gonadotrophin, monophosphoryl lipid A+myobacterium cell wall sk, mopidamol, multiple drug resistance gene inhibitor, multiple tumor suppressor 1-based therapy, mustard anticancer agent, mycaperoxide B, mycobacterial cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagrestip, naloxone+pentazocine, napavin, naphterpin, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidant, nitrullyn, O6-benzylguanine, octreotide, okicenone, oligonucleotides, onapristone, ondansetron, oracin, oral cytokine inducer, ormaplatin, osaterone, oxaliplatin, oxaunomycin, 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 complex, porfimer sodium, porfiromycin, prednisone, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based immune modulator, protein kinase C inhibitor, microalgal, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyrazoloacridine, pyridoxylated hemoglobin polyoxyethylene conjugate, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitor, retelliptine demethylated, rhenium Re 186 etidronate, rhizoxin, ribozymes, RII retinamide, rogletimide, rohitukine, romurtide, roquinimex, rubiginone Bl, ruboxyl, safmgol, saintopin, SarCNU, sarcophytol A, sargramostim, Sdi 1 mimetics, semustine, senescence derived inhibitor 1, sense oligonucleotides, signal transduction inhibitors, signal transduction modulators, single chain antigen-binding protein, sizofiran, sobuzoxane, sodium borocaptate, sodium phenylacetate, solverol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitor, stem-cell division inhibitors, stipiamide, stromelysin inhibitors, sulfinosine, superactive vasoactive intestinal peptide antagonist, suradista, suramin, swainsonine, synthetic glycosaminoglycans, tallimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, tellurapyrylium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, thaliblastine, thiocoraline, thrombopoietin, thrombopoietin mimetic, thymalfasin, thymopoietin receptor agonist, thymotrinan, thyroid stimulating hormone, tin ethyl etiopurpurin, tirapazamine, titanocene bichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector system, erythrocyte gene therapy, velaresol, veramine, verdins, verteporfin, vinorelbine, vinxaltine, vitaxin, vorozole, zanoterone, zeniplatin, zilascorb, and zinostatin stimalamer.
- In some embodiments, the anti-cancer agent is one or more of an antracycline (e.g., doxorubicin or epirubicin), cyclophosphamide, a platinum agent (e.g., cisplatin, carboplatin, oxaliplatin), a taxane (e.g., paclitaxel or docetaxel), methotrexate, 5-fluorouracil, trastuxumab, pertuzumab, vinorelbine, capecitabine, gemcitabine, mitoxantrone, ixabepilone, reibulin, an anti-hormone therapy (e.g., tamoxifen, anastrazole, exemestrane, letrozole), etoposide, irinotecan, vinblastine, pemetrexed, bevacizumab, cetuximab, an EGFR inhibitor (e.g., erlotinib), an EML4-ALK kinase inhibitor (e.g., crixotinil), estramustine, cytarabine, a demethylating agent (e.g., 5-azacytidine, decitabine), an immunomodulator (e.g., lenolidamide, pomalidomide), a corticosteroid, bleomycin, adriamycin, benamustin, fludarabine, a growth factor (GCSH, GM-CSF, EPO), and bortezomib.
- Specific combinations of RARα selective agonists and additional anti-cancer agents useful in the treatment of cancer are listed below in Table 1. The listed drug combinations can be administered at the same time, at different times, in the same composition, in different compositions, in alternating times (1 week of RARα selective agonist followed by 1 week of another anti-cancer agent, etc.), or at any administration schedule established by a healthcare professional.
-
TABLE 1 Cancer Exemplary Drug combination Breast RARα selective agonist + an anthracycline (e.g., doxorubicin or epirubicin) + cyclophosphamide with or without a platinum agent (e.g., cisplatin or carboplatin) RARα selective agonist + an anthracycline + taxane (e.g., paclitaxel or docetaxel) with or without a platinum agent RARα selective agonist + cyclophosphamide + methotrexate + 5-fluorouracil with or without a platinum agent RARα selective agonist + an anthracycline + cyclophosphamide + 5-fluorouracil with or without a platinum agent RARα selective agonist + trastuzumab + a taxane RARα selective agonist + pertuzumab + trastuzumab + a platinum agent RARα selective agonist + vinorelbine with or without a platinum agent RARα selective agonist + capecitabine with or without a platinum agent RARα selective agonist + gemcitabine with or without a platinum agent RARα selective agonist + mitoxantrone with or without a platinum agent RARα selective agonist + ixabepilone with or without a platinum agent RARα selective agonist + eribulin with or without a platinum agent RARα selective agonist + an anthracycline with or without a platinum agent RARα selective agonist + a platinum agent RARα selective agonist +a taxane with or without a platinum agent RARα selective agonist + trastuzumab or pertuzumab with or without a platinum agent RARα selective agonist + cyclophosphamide with or without a platinum agent RARα selective agonist + methotrexate with or without a platinum agent RARα selective agonist + 5-fluorouracil with or without a platinum agent RARα selective agonist + a combination of two or more of a platinum agent, a taxane, gemcitabine, vinorelbine, capecitabine, cyclophosphamide, metotrexate, 5-fluorourocil, an anthracycline, trastuzumab, pertuzumab, mitoxantrone, ixabepilone, or eribulin. RARα selective agonist + trastuzumab RARα selective agonist + anti-hormone therapy (e.g., tamoxifen, anastrazole, exemestrane, letrozole) Lung RARα selective agonist + a platinum agent RARα selective agonist +etoposide RARα selective agonist + irinotecan RARα selective agonist + a platinum agent + etoposide RARα selective agonist + a platinum agent + irinotecan RARα selective agonist + a taxane RARα selective agonist + gemcitabine RARα selective agonist + vinorelbine RARα selective agonist + capecitabine RARα selective agonist + vinblastine RARα selective agonist + pemetrexed RARα selective agonist + bevacizumab RARα selective agonist + cetuximab RARα selective agonist + a combination of two or more of a platinum agent, etoposide, irinotecan, a taxane, gemcitabine, vinorelbine, capecitabine, vinblastine, pemetrexed, bevacizumab, or cetuximab RARα selective agonist + EGFR inhibitor (e.g.,erlotinib) RARα selective agonist + EML4- ALK kinase inhibitor (e.g., crizotinil) Pancreas RARα selective agonist + gemcitabine RARα selective agonist + erlotinib RARα selective agonist + 5-fluourouracil RARα selective agonist + irinotecan RARα selective agonist + a platinum compound RARα selective agonist + oxaliplatin RARα selective agonist + capecitabine RARα selective agonist +a taxane RARα selective agonist + a combination of two or more of a platinum agent, irinotecan, a taxane, gemcitabine, capecitabine, erlotinib, 5-fluorouracil, or oxaliplatin. Prostate RARα selective agonist +etoposide RARα selective agonist + a platinum agent RARα selective agonist + a taxane RARα selective agonist + vinorelbine RARα selective agonist + vinblastine RARα selective agonist + mitoxantrone RARα selective agonist + cabazitaxel RARα selective agonist + estramustine RARα selective agonist + an anthracycline RARα selective agonist + a combination of two or more of a platinum agent, etoposide, a taxane, vinorelbine, vinblastine, mitoxantrone, cabazitaxel, estramustine, or an anthracycline Hematological Malignancies RARα selective agonist + etoposide RARα selective agonist + an anthracycline (e.g., idarubicin, daunorubicin, mitoxantrone) RARα selective agonist + cytarabine RARα selective agonist + a combination of an anthracycline, cytarabine and etoposide RARα selective agonist + demethylating agent (5-azacytidine or decitabine) RARα selective agonist + small molecule inhibitors (e.g., thyrosine kinase inhibitors including BCR-ABL inhibitors, Flt3 inhibitors or cKit inhibitor, IDH½ inhibitors, JAK2 inhibitors, BTK inhibitors) RARα selective agonist + immunotherapeutic agents (monoclonal antibodies such as anti-CD33, anti-CD20, anti-CD19, anti-CD30 or with PD1 inhibitors or CTL4 inhibitors) RARα selective agonist + immunomodulatory drugs such as lenolidamide, pomalidomide, and their derivatives RARα selective agonist + cyclophosphamide RARα selective agonist + bevacizumab RARα selective agonist + vincristine RARα selective agonist + a corticosteroid RARα selective agonist + bleomycin RARα selective agonist + adriamycin RARα selective agonist + bendamustin RARα selective agonist + fludarabine RARα selective agonist + growth factors including GCSF, GM-CSF and Epo RARα selective agonist + a combination of two or more of combinations listed above. RARα selective agonist + bortezomib - The effectiveness of cancer therapy is typically measured in terms of “response.” The techniques to monitor responses can be similar to the tests used to diagnose cancer such as, but not limited to:
- A lump or tumor involving some lymph nodes can be felt and measured externally by physical examination.
- Some internal cancer tumors will show up on an x-ray or CT scan and can be measured with a ruler.
- Blood tests, including those that measure organ function can be performed.
- A tumor marker test can be done for certain cancers.
- Regardless of the test used - whether blood test, cell count, or tumor marker test, it is repeated at specific intervals so that the results can be compared to earlier tests of the same type.
- Response to cancer treatment is defined several ways:
- Complete response - all of the cancer or tumor disappears; there is no evidence of disease. A tumor marker (if applicable) may fall within the normal range.
- Partial response - the cancer has shrunk by a percentage but disease remains. A tumor marker (if applicable) may have fallen but evidence of disease remains.
- Stable disease - the cancer has neither grown nor shrunk; the amount of disease has not changed. A tumor marker (if applicable) has not changed significantly.
- Disease progression - the cancer has grown; there is more disease now than before treatment. A tumor marker test (if applicable) shows that a tumor marker has risen.
- There are two standard methods for the evaluation of solid cancer treatment response with regard to tumor size (tumor burden), the WHO and RECIST standards. These methods measure a solid tumor to compare a current tumor with past measurements or to compare changes with future measurements and to make changes in a treatment regimen. In the WHO method, the solid tumor’s long and short axes are measured with the product of these two measurements is then calculated; if there are multiple solid tumors, the sum of all the products calculated. In the RECIST method, only the long axis is measured. If there are multiple solid tumors, the sum of all the long axes measurements is calculated. However, with lymph nodes, the short axis is measured instead of the long axis.
- In some embodiments of the current method, the tumor burden of a treated patient is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or any other range bound by these values.
- In other embodiments, the 1-year survival rate of treated individual is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or any other range bound by these values.
- In other embodiments, the 5-year survival rate of treated individual is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or any other range bound by these values.
- In other embodiments, the 10-year survival rate of treated individual is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or any other range bound by these values.
- In yet other embodiments, the subject has a sustained remission of at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 22 months, at least 24 months, at least 27 months, at least 30 months, at least 33 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, or at least 60 months or more.
- As used herein, the term “substantially free of cancer” refers to a subject which does not have clinical evidence of cancer or cancer cells, or cancer stem cells.
- In other embodiments, the method may help to treat or alleviate conditions, symptoms, or disorders related to cancer. In some embodiments, these conditions or symptoms may include, but are not limited to, anemia, asthenia, cachexia, Cushing’s Syndrome, fatigue, gout, gum disease, hematuria, hypercalcemia, hypothyroidism, internal bleeding, hair loss, mesothelioma, nausea, night sweats, neutropenia, paraneoplastic syndromes, pleuritis, polymyalgia rheumatica, rhabdomyolysis, stress, swollen lymph nodes, thrombocytopenia, Vitamin D deficiency, or weight loss. In other embodiments, the administration of the RARα selective agonist prolongs the survival of the individual being treated.
- Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells (PCs) within the BM and their production of monoclonal immunoglobulin (Ig). Novel therapies, including proteasome inhibitors, have significantly extended the survival of patients with MM but have failed to achieve a cure. Increasing evidence demonstrates that interactions with the BM microenvironment play a critical role in the survival of MM cells during chemotherapy. However, the mechanisms mediating this BM niche-dependent chemoprotection are incompletely understood and remain a critical area of research.
- There exist MM cells that resemble mature B cells and are resistant to bortezomib (BTZ). Like their normal B cell counterparts, these CD138- MM cells are capable of clonogenic growth and differentiation into CD138+ PCs. Moreover, these cells are enriched during minimal residual disease (MRD), suggesting a critical role in disease relapse. Differential BTZ sensitivity of CD138+ and CD138- MM cells may be explained by their secretory activity. As a result of their abundant Ig production, CD138+ PCs are highly dependent on an intact proteasome pathway to degrade improperly folded proteins. Conditions that disrupt protein degradation by the proteasome activate a cellular stress pathway known as the unfolded protein response (UPR), which counteracts ER stress by decreasing protein synthesis and promoting protein degradation. If homeostasis cannot be reestablished, UPR activation eventually leads to apoptosis. On the other hand, CD138- MM cells exhibit limited Ig production and low ER stress and are less dependent on proteasome-mediated degradation of misfolded proteins.
- Cell cultures. All cell lines were purchased from the American Type Culture Collection. H929, MM1s, and U266 cells were cultured in RPMI 1640 with 10% FCS (Sigma-Aldrich), 2 mM L-glutamine, and 100 µg/ml penicillin-streptomycin (P/S). OP-9 cells were cultured in α-MEM, 20% FCS, L-glutamine, and P/S. Cell lines were authenticated by short-tandem repeat profiling.
- Primary MM cells were obtained from patients with newly diagnosed or relapsed MM under an IRB-approved protocol at The Johns Hopkins University. Briefly, mononuclear cells were isolated from fresh BM aspirates by density gradient centrifugation (Ficoll-Paque); CD138+ cells were then selected via magnetic beads and columns and incubated in
RPMI 1640, 10% FCS, L-glutamine, and P/S at 37° C. - Primary human BM stromal cells were derived from aspirates collected from healthy donors under an IRB-approved protocol at Johns Hopkins. Briefly, total mononuclear cells isolated from BM aspirates were cultured in Iscove’s modified Dulbecco’s medium (IMDM) supplemented with 10% horse serum, 10% FCS, 10-5 M hydrocortisone 21-hemisuccinate, P/S, and 0.1 mM β-mercaptoethanol (β-ME) (FBMD1 media). The following day, cells in suspension were removed by washing twice with PBS, and the media were replaced. Attached stromal cells were incubated at 33° C. until a confluent monolayer was obtained. Mouse primary BM stromal cells were isolated following the same protocol, after isolation of total BM mononuclear cells from mouse femurs.
- Vectors and viral supernatants. To generate Smo-KO and WT stroma, BM stromal cells were derived from Smofl/fl mice and transduced with the retroviral vector PIG-Cre encoding Cre-recombinase (Addgene; catalog 50935) or a control vector (Addgene; catalog 18751), respectively. Successfully infected cells were selected using 4 µg/ml puromycin for 5 days and confirmed by expression of GFP via flow cytometry. The pLenti-CMV-LUC-Puro lentiviral vector (plasmid 17477) was used to generate H929 Luc+ cells.
- To generate CYP26A1-overexpressing stromal cells, WT and Smo-KO stromal cells were transduced with the lentiviral vector pBABE-neo (Addgene; catalog 1767) that had been engineered to encode CYP26A1. Briefly, Cyp26a1 cDNA (Origene) was amplified via PCR using primers incorporating the restriction sites BamHI and EcoRI and cloned into the pCR2.1 vector. Cyp26a1 cDNA was confirmed via Sanger sequencing, and the fragment was isolated after digestion with the restriction enzymes BamHI and EcoRI and subcloned into the corresponding sites of the pBABE vector. Lentiviral particles were produced as previously described. Successfully infected stromal cells were selected using 3 µg/ml G-418 for 10 days, and expression of Cyp26a1 was confirmed by qRT-PCR.
- Coculture experiments. 24-well plates were coated with 0.1% gelatin in PBS for 30 min at 37° C. The gelatin solution was removed, and the stromal cells were cultured overnight at a density of 5×104 cells/well to obtain a confluent monolayer. At that time, MM cell lines or primary MM cells (1×105 in 2 ml) were added to the stroma cultures. The stroma cocultures were incubated at 37° C. in RPMI containing 10% FCS, L-glutamine, and P/S, with or without AGN19194310 (1 µM for 5 days), R115866 (1 µM for 5 days), IRX5183 (1 µM for 5 days), or BTZ (2.5 nM for 48 hr).
- Transwell experiments. For Transwell experiments, 6-well plates were coated with 0.1% gelatin in PBS for 30 min at 37° C. The gelatin solution was removed, and the stromal cells were cultured overnight in FBMD1 media at a density of 10×104 cells/well in 2 ml of media to obtain a confluent monolayer. At that time, Transwell inserts (Corning) were placed over the stroma cultures, and MM cell lines (1×106 in 1 ml) were seeded in the Transwell for 24 hr at 37° C. Following this incubation, Transwell and MM cells were removed, and stromal cells were detached from the wells and analyzed by qRT-PCR for CYP26 expression.
- Mobilization experiments. MM cells were separated from BM stromal cells by gently pipetting several times around the well. Detached cells were centrifuged, resuspended in fresh media, and incubated in a 24-well plate for 1 hr at 37° C. During this short incubation period, contaminating stromal cells attached to the well, while MM cells remained in suspension. MM cells were then recovered by gently pipetting. This protocol was used for qRT-PCR and CFU coculture experiments. The purity achieved using this protocol was confirmed by flow cytometry to be 98%-99% MM cells and less than 2% contaminating stroma.
- Clonogenic assays. After treatment, MM cells were collected, washed with PBS, and plated at a density of 5,000 cells/ml in 1 ml of 1.32% methylcellulose supplemented with 30% FBS, 10% BSA, L-glutamine, P/S, and 0.1 mM β-ME. Cells were plated in triplicate in 35-mm culture dishes, incubated at 37° C., and scored for the presence of
colonies 14 days later. - qRT-PCR. Total RNA was extracted using the RNeasy Mini Kit (QIAGEN) according to the manufacturer’s instructions. cDNA was synthesized by reverse transcription using the iScript cDNA Synthesis Kit (Bio-Rad). qRT-PCR was performed with iTaq SYBR Green Supermix (Bio-Rad) using sequence specific primers. Gene expression was normalized to GAPDH, and relative quantification was calculated using ΔΔCt. All experiments were performed in duplicate and run on the Bio-Rad CFX96 machine.
- Flow cytometry. Following treatment, MM cells were collected, washed with PBS, and stained for 15 min at room temperature with phycoerythrin-conjugated (PE-conjugated) anti-CD138. Cells were washed to remove unbound antibody and evaluated in a FACSCalibur system (BD Biosciences). Stromal cells were identified by GFP expression, and viable cells were identified using 7-aminoactinomycin D (7-AAD). To calculate cell numbers, live GFP- cells were normalized to calibration beads.
- Mouse xenografts. 1×106 H929 Luc+ cells and 1×106 mouse BM stromal cells were resuspended in 100 µl Matrigel, diluted with RPMI (1:1), and injected subcutaneously into 16-week-old male NSG mice. After 4 days, treatment with BTZ (0.5 mg/kg i.p. twice weekly) and IRX (10 mg/kg i.p. daily) was initiated. Tumor burden was assessed by bioluminescence using the In Vivo Imaging System (PerkinElmer). For imaging, mice were exposed to 120 mg/kg D-luciferin via intraperitoneal injection 10-5 min before imaging and were anesthetized using isoflurane. Images were analyzed with Living Image Software, version 2.5 (PerkinElmer), and data were quantified as photons/second.
- For the systemic MM model, 2×106 Luc+/GFP+ H929 cells were injected via the tail vein into 16-week-old male NSG mice. After engraftment, as determined by an exponential increase in bioluminescence, mice were treated with BTZ (0.5 mg/kg i.p.) twice weekly and with IRX (10 mg/kg) once daily. Tumor burden was assessed by bioluminescence, as above.
- Statistics. First evaluated was whether the treatment groups were different from the controls using 1-way ANOVA. If the ANOVA test yielded a statistically significant result, then the difference between the control group and each treatment group was evaluated, with the P values adjusted for multiple comparisons using Dunnett’s test. For experiments in which only 2 sets of data were analyzed, statistical significance was evaluated using an unpaired, 2-tailed Student’s t test. Pearson’s R value for correlation and P values were calculated using GraphPad Prism 7(GraphPad Software).
- The BM niche limits PC differentiation by modulating retinoid signaling. A population of MM progenitors, phenotypically similar to B cells, is intrinsically resistant to BTZ and contributes to MRD and relapse. To investigate whether the BM niche plays a role in determining the phenotype of MM cells, the mRNA expression of B cell and PC markers in MM H929 cell lines (
FIGS. 1A-D ) and MM CD138+ primary cells (FIGS. 1E-H ) was analyzed following coculture with mouse BM stroma using human-specific primers. B cell lymphoma 6 (BCL6), a transcriptional repressor that promotes self-renewal of germinal center B cells and prevents PC differentiation, was upregulated in the presence of BM stromal cells (FIGS. 1A, 1E ). In contrast, coculture of MM cells with BM stroma decreased the mRNA expression of B lymphocyte-induced maturation protein 1 (BLIMP1) and spliced X box-binding protein 1 (XBP1s) (FIGS. 1B, C, F, G ), which are critical mediators of PC differentiation. Similarly, C/EBP homologous protein (CHOP), a key component of the UPR pathway, was downregulated in the presence of BM stromal cells (FIGS. 1D, H ). - The BM niche regulates hematopoietic stem cell (HSC) differentiation by expressing the retinoid-inactivating enzyme CYP26. CYP26 enzymes were highly expressed in BM mesenchymal cells, while their expression was barely detectable in MM cells. Since retinoid signaling promotes PC differentiation and potentiates Ig secretion, it was determined whether stromal CYP26 is responsible for inducing a B cell phenotype in MM cells. To this end, coculture conditions were treated with the CYP26 inhibitor R115866 (R115) or the CYP26-resistant RA receptor α-selective (RARα-selective) retinoid IRX5183 (IRX). Incubation of stroma cocultures with either R115 or IRX restored all markers to levels comparable to those of liquid control conditions (
FIGS. 1A-H ). Moreover, treatment of MM cells with the pan-RAR antagonist AGN194310 (AGN) mimicked the changes induced by BM stromal cells (FIGS. 1A-H ), limiting PC differentiation. - Expression of CD138 is a hallmark of normal PC differentiation as well MM PCs. Consistent with mRNA levels of PC markers, surface CD138 expression was markedly decreased by coculture with BM stromal cells or incubation with AGN. Incubation of BM stromal cell cocultures with R115 or IRX restored CD138 expression in MM cells. R115 did not significantly affect the expression of differentiation markers in liquid conditions by quantitative reverse transcription-PCR (qRT-PCR) or flow cytometry, while IRX induced comparable changes, irrespective of the presence or absence of BM stroma. Taken together, these data suggest that retinoid signaling promotes PC differentiation of MM cells and that this process is blocked by stromal CYP26-mediated metabolism of RA.
- A RA-low microenvironment induces BTZ resistance. To determine whether decreased retinoid signaling contributes to BTZ resistance within the BM niche, MM cell lines and MM CD138+ primary cells were incubated with BM stroma for 5 days, followed by BTZ treatment. In the absence of BM stroma (liquid), MM cells were highly sensitive to BTZ (
FIGS. 2A-B ). However, incubation with BM stroma induced BTZ resistance, which was overcome by CYP26 inhibition via R115 or by the CYP26-resistant retinoid IRX. Moreover, treatment of MM cells with the pan-RAR antagonist AGN mimicked the changes induced by BM stromal cells (FIG. 3 ), decreasing BTZ sensitivity. - Strategies to overcome microenvironment-dependent chemoprotection have focused on mobilization of cancer cells from the BM niche into the peripheral circulation. It was analyzed whether the change in phenotype and subsequent BTZ resistance of MM cells were lost upon separation from the BM stroma, a process that mimics mobilization. To this end, H929 cells were separated from BM mesenchymal cells following a 5-day stroma coculture, incubated in fresh media (RPMI with 10% FBS) for 0 to 48 hr, and then treated with BTZ. Interestingly, MM cells remained partially resistant to BTZ for up to 48 hr following detachment from stroma (
FIG. 3 ). Moreover, treatment of the coculture conditions with R115 prevented the development of a BTZ-resistant phenotype (FIG. 3 ). Thus, microenvironment-dependent BTZ resistance induced by the change in MM cell phenotype may not immediately be reversed by tumor mobilization. - To test whether retinoids can enhance BTZ activity in MM, a systemic MM xenograft was developed by injecting 2×106 H929 luciferase+ (Luc+) cells via the tail vein of nonobese, diabetic, severe combined immunodeficiency IL-2 receptor γ-KO (NSG) mice. The animals were randomized to receive IRX, BTZ, or a combination of both, and disease burden was followed weekly by bioluminescence imaging (
FIG. 4 ). Mice treated with BTZ showed decreased tumor growth compared with untreated controls; however, some MM cells remained resistant to BTZ, as demonstrated by the continued increase in bioluminescence. Similarly, mice treated with IRX monotherapy showed a decrease in tumor burden compared with untreated mice. Most important, IRX sensitized MM cells to BTZ, leading to a significant (P < 0.01) decrease in disease burden. Collectively, these data suggest that an RA-low microenvironment created by stromal CYP26 induces a BTZ-resistant phenotype, which is maintained even after displacement from the BM niche. - MM cells induce stromal CYP26. Recent studies have demonstrated the existence of a bi-directional crosstalk, in which not only stromal cells provide a protective microenvironment, but also cancer cells actively adapt and build a reinforced niche. Thus, it was determined whether MM cells reinforce a protective microenvironment by strengthening the ability of BM stroma to inactivate retinoids. Stromal CYP26 expression was analyzed by qRT-PCR in BM mesenchymal cells following a 24-hr coculture with MM cells. The isoenzyme CYP26A1 was highly upregulated by all 3 MM cell lines tested (
FIGS. 5A-C ). In contrast, the isoenzyme CYP26B1 showed little to no changes in mRNA levels. Conditioned media derived from MM cells also upregulated CYP26A1 in BM stromal cells, although to a lesser extent. This could be explained by the presence of physical interactions in coculture experiments, or the lack of continuous production of soluble ligands by MM cells in conditioned media experiments. Consistent with the latter, stromal CYP26A1 was highly upregulated when MM and BM stromal cells were separated by a Transwell that prevented physical contact but allowed the diffusion of soluble factors (FIGS. 5A-C ). - MM cells produce a variety of soluble factors including cytokines (IL-1, IL-3, IL-6, TNF-α) as well as Hedgehog ligands such as sonic hedgehog (SHH), which could impact the BM stromal compartment. Therefore, it was determined whether any of these factors was responsible for the observed upregulation of CYP26A1 on BM stromal cells. Of the soluble factors tested, only SHH produced a sustained overexpression of CYP26A1, while IL-1, IL-3, IL-6, and TNF-α had no significant effects. Whereas SHH is expressed by BM stromal cells and thus may be able to activate the Hedgehog pathway in an autocrine manner, its expression was considerably higher in MM cells compared with that detected in BM stroma, suggesting that paracrine activation may play a dominant role. Consistent with this, there was a statistically significant correlation between the mRNA levels of SHH in MM cells and activation of stromal Hedgehog signaling as determined by protein patched homolog 1 (PTCH1) expression. Moreover, activation of stromal Hedgehog significantly correlated with CYP26A1 upregulation. Specifically, MM1S cells with the highest expression of SHH also induced the highest expression of both PTCH1 and CY26A1 in stromal cells. SHH has a half-life of less than 1 hr, which may explain the reduced effect of MM-conditioned media on stromal CYP26A1 expression compared with that observed in coculture and Transwell experiments.
- To confirm the role of paracrine Hedgehog on this interaction, smoothened (Smo), a membrane receptor that transduces SHH signaling, was knocked out at the genomic level in the mesenchymal compartment. For this, BM mesenchymal cells derived from Smofl/fl mice were transduced with a retroviral vector encoding Cre recombinase (Smo-KO stroma). Mouse Smofl/fl stromal cells transduced with an empty retroviral vector were used as a control (WT stroma). The transduced BM stromal cells were cocultured with MM cells for 24 hr. As expected, Smo-KO stroma had a decreased ability to upregulate Cyp26a1 in response to MM cells compared with WT stroma (
FIGS. 6A-C ). Similarly, the SMO inhibitor cyclopamine partially overcame stromal Cyp26a1 upregulation by MM cells. These data suggest that MM cells modulate stromal CYP26 expression at least in part via paracrine SHH. - Paracrine Hedgehog produced by MM cells reinforces a protective microenvironment. Given the observations that stromal CYP26 activity may be responsible for BTZ resistance in MM cells, it was assessed whether paracrine Hedgehog secreted by MM cells reinforces a chemoprotective niche by regulating retinoid metabolism. It was first investigated whether modulation of Hedgehog signaling paralleled the retinoid-dependent phenotypes observed previously. Disruption of paracrine Hedgehog signaling in Smo-KO stroma cocultures partially restored PC differentiation (downregulation of BCL6 and upregulation of BLIMP1, XBP1, and CHOP) in H929 (
FIGS. 9A-D ) and primary CD138+ MM cells (FIGS. 9E-H ). Surface expression of CD138 was also restored in the presence of Smo-KO stroma. As expected, these findings were associated with an increased sensitivity to BTZ of MM cells treated in the presence of Smo-KO stroma compared with WT stroma. - To demonstrate that paracrine Hedgehog indeed induces a BTZ-resistant phenotype by increasing the ability of BM stroma to inactivate retinoids, Cyp26a1 expression in Smo-KO stroma was rescued via lentivirus-mediated gene transfer (pBABE-Cyp26a1) in order to achieve comparable CYP26A1 levels in WT (WT-Cyp26a1) and Smo-KO (Smo-KO-Cyp26a1) stromal cells. If the role of paracrine Hedgehog was independent of retinoid signaling, the relative inability of Smo-KO stroma to induce a B cell phenotype and BTZ resistance should have persisted even after Cyp26a1 upregulation. However, Cyp26a1 overexpression rescued the ability of Smo-KO stroma to induce a B cell phenotype and restored the expression of differentiation markers and BTZ resistance to levels comparable to those detected in WT and WT-Cyp26a1 stroma coculture conditions. This finding is consistent with the hypothesis that paracrine Hedgehog reinforces a protective niche via Cyp26a1 upregulation.
- To study to what extent an RA-low environment created by the BM stroma and enhanced by MM cells via paracrine Hedgehog signaling contributes to BTZ resistance, a xenograft model of MM-niche interactions was developed. Each mouse carried 2 subcutaneous tumors consisting of H929 Luc+ cells and either WT (anterior tumors) or Smo-KO stroma (posterior tumors). Mice were treated with IRX (10 mg/kg i.p. daily), BTZ (0.5 mg/kg i.p. twice weekly), or a combination of both. The growth of tumors bearing WT or Smo-KO stroma was not different in untreated or IRX-treated groups (
FIGS. 7 and 8 ). Consistent with in vitro data, tumors with WT stroma were refractory to BTZ treatment, as determined by an exponential increase in bioluminescence, while tumors carrying Smo-KO stroma showed a significant response (FIG. 8 ). Moreover, the combination of IRX and BTZ resulted in a significant and equivalent response, regardless of the phenotype of the stromal compartment (FIG. 8 ). While some tumors in the treatment group receiving combined IRX and BTZ appeared to have regressed completely, even after anatomical study, this was not the case for all the mice in this group. Flow cytometric analyses of the tumors after treatment revealed no differences in the in vivo growth of WT or Smo-KO stroma. Taken together, these data suggest that paracrine Hedgehog secreted by MM cells modulates retinoid signaling and BTZ sensitivity in the BM niche via CYP26A1 upregulation. - Given their high secretion of Ig, PCs are particularly sensitive to proteasome inhibition, and this accounts for the high remission rates achieved in MM patients treated with this family of drugs. Nonetheless, BTZ has failed to achieve a cure. A population of MM cells, phenotypically similar to B cells, survive BTZ treatment and are able to differentiate into PCs and recapitulate the original disease. Despite efficient elimination of MM PCs, these MM B cells survive BTZ treatment and become the predominant cell population during MRD. Consequently, new therapeutic strategies targeting MM B cells are required. A retinoid-low microenvironment created by stromal CYP26 maintained an immature, BTZ-resistant phenotype in MM. Thus, these data reveal a therapeutic opportunity to overcome BTZ resistance in the MM microenvironment using CYP26-resistant retinoids.
- Despite being extensively studied in many hematological malignancies, the use of retinoids as differentiation therapy has proved beneficial only in patients with acute promyelocytic leukemia (APL). CYP26 expression by BM stromal cells may explain the lack of a clinical benefit of natural retinoids, despite their in vitro activity. Recent studies have highlighted the efficacy of CYP-resistant synthetic retinoids in differentiating cancer cells and sensitizing them to targeted therapy. For instance, AM80 differentiates FMS-
like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) acute myeloid leukemia (AML) cells and increase their sensitivity to FLT3 inhibitors. Similarly, synthetic retinoids reverse a stem cell phenotype in BCR-ABL1+ leukemic lymphoblasts and substantially increase their responsiveness to tyrosine kinase inhibitor (TKI) therapy in vivo. Such strategies to bypass stromal CYP26 could expand the clinical effectiveness of retinoid therapy. - MM cells utilize physical contacts to maintain drug resistance and survive within the BM niche. Thus, therapeutic strategies to overcome stromal chemoprotection have focused on mobilization of malignant cells from the BM niche by targeting adhesion molecules or chemokines such as CXCR4. MM cells exposed to a retinoid-low microenvironment acquire a BTZ-resistant phenotype that is maintained even after these cells are displaced from their niche. Initial clinical studies have shown improved response rates in relapse/refractory patients receiving the CXCR4 inhibitor plerixafor in combination with BTZ; however, this data suggest that such mobilization approaches may be insufficient to eliminate MM B cells.
- Recent studies have demonstrated the existence of a bidirectional communication, in which not only stromal cells provide a chemoprotective niche, but also cancer cells actively shape and reinforce their microenvironment. The role of paracrine Hedgehog has been studied extensively in solid malignancies. In this system, ligands secreted by cancer cells activate the Hedgehog pathway in neighboring stromal cells, enhancing their chemoprotective properties via incompletely understood mechanisms. This data suggest that paracrine Hedgehog may work at least in part by increasing the ability of stroma to inactivate retinoids through upregulation of CYP26 and thus to maintain a BTZ-resistant phenotype in MM. Interestingly, CYP26 upregulation is associated with an “activated stromal subtype” and a significantly worse prognosis in patients with pancreatic cancer, a disease in which paracrine Hedgehog signaling is well established. The extent to which Hedgehog ligands produced by cancer cells contribute to this “activated” stromal phenotype and high CYP26 levels is unknown. Moreover, BM mesenchymal cells migrate and become a relevant cell population in the stromal compartment of these tumors.
- The endosteal region is the primary niche of MM, AML, and micrometastatic disease from solid tumors. Within the osteoblastic region, these cancer cells maintain a quiescent, stem cell phenotype and are protected from chemotherapy-induced apoptosis. It is likely that these cancer cells rely on the same cues from the BM microenvironment as normal hematopoietic stem cells do to survive chemotherapy and perpetuate the disease. The BM microenvironment protected MM and AML cells by directly inactivating various chemotherapy agents via expression of CYP3A4 and other detoxifying enzymes. Another potential mechanism of microenvironment-mediated drug resistance is now demonstrated: creation of a retinoid-low niche that maintains a drug-resistant B cell phenotype. A CYP26-resistant retinoid potentiated the activity of BTZ against MM in the BM niche provides a therapeutic opportunity to bypass this mechanism of resistance.
- All-trans retinoic acid (ATRA), acting through RARα, causes terminal differentiation and apoptosis of non-APL AML cells in vitro but is clinically ineffective against AML. The BM stroma, which expresses inducibly high levels of CYP26, metabolically inactivates ATRA and provides a protected environment for AML cancer stem cells. Synthetic, CYP26-resistant RARα agonists, such as IRX5183 and AM80, should be able to bypass stroma-mediated protection of AML cells and differentiate the cancer stem cells resident in the protected environment of bone marrow niche. To test these hypotheses, clonogenic growth experiments were conducted in the non-APL AML cell lines OCI-
AML 3 and Kasumi-1 and APL NB4 cells, which were treated with ATRA, IRX5183, and AM80 in the presence or absence of stroma. ATRA inhibited clonogenic growth only in the absence of stroma. In contrast, IRX5183 inhibited clonogenic growth to a similar extent in the presence or absence of stroma (FIGS. 10A-C ). AM80 also inhibited clonogenic growth in the presence of stroma but not as effectively as IRX5183. These data indicate that CYP26-resistant, RARα agonists such as IRX5183 may be effective treatments for AML by overcoming stromal mechanisms of drug resistance. - Acute myeloid leukemia (AML) is successfully treated in only 30-40% of younger patients and very few older patients with standard chemotherapy regimens. Given the clinical activity of all-trans retinoic acid (ATRA; retinoic acid, RA) in acute promyelocytic leukemia (APL), ATRA was considered an attractive therapeutic strategy for other AML subtypes. APL, and most non-APL AMLs undergo terminal differentiation and are therefore successfully treated by ATRA in vitro. However, ATRA has not proven effective in non-APL AMLs in clinical trials.
- Retinoic acid (RA) plays a significant role in the differentiation of hematopoietic stem cells (HSCs). The cytochrome P450 enzyme CYP26, expressed in bone marrow (BM) stromal cells, inactivates RA, thereby limiting differentiation of HSCs. Several AML cell lines, both APL and non-APL, are sensitive to RA-induced differentiation, but this effect was abrogated in the presence of BM stroma. Thus, it may be useful to treat AML with a retinoid that is resistant to metabolism by the CYP26 pathway. IRX5183 is a RARα selective agonist which is resistant to CYP26 metabolism. Use of IRX5183 in AML provides a novel targeted approach to this disease, which has the potential to change the prognosis of this and other hematologic malignancies. Thus, a phase I/II clinical trial will be conducted of IRX5183 in relapsed/refractory AML and high risk myelodysplastic syndrome (HR-MDS).
- Dose escalation phase primary objectives:
- 1) Evaluate safety and toxicity associated with administration of IRX5183 in patients with relapsed and refractory AML by determining the dose limiting toxicities (DLT) and maximally-tolerated dose (MTD).
- 2) Determine pharmacokinetic (PK) parameters of IRX5183 in the peripheral blood.
- Dose escalation phase secondary objectives:
- 1) Determine the PK parameters of IRX5183 in the bone marrow.
- 2) Define differentiation profiles associated with IRX5183, BM cellular retinoid concentrations, blast counts, and cytogenetics at different dose levels.
- Dose expansion phase primary objectives:
- 1) Define differentiation markers, BM retinoid concentrations, blast counts, and cytogenetics in AML and HR-MDS patients at the optimal dose level.
- 2) Obtain preliminary efficacy data of IRX5183 in terms of complete response (CR), partial response (PR), and hematological improvement (HI) in both cohorts of patients.
- Dose expansion phase secondary objectives:
- 1) Define toxicity profiles of IRX5183 at the optimal dose in both patient cohorts.
- 2) Obtain data on correlations between IRX5183-induced differentiation and toxicity and clinical responses.
- Eligibility criteria - dose escalation/determination. This phase will only recruit patients with AML:
- 1. Patients must be able to understand and voluntarily sign an informed consent form.
- 2. Age 18-70 years at the time of signing the informed consent.
- 3. Able to adhere to the study visit schedule and other protocol requirements.
- 4. Life expectancy of greater than 6 months.
- 5. Must have pathologically confirmed AML with one or two prior courses of induction chemotherapy or hypomethylating agent therapy or relapsed after complete remission, before or after allogeneic bone marrow transplant, AND no plans for further intensive chemotherapy.
- 6. Patients must not have received any other treatment for their disease (aside from hydroxyurea for control of blast count in AML patients), including hematopoietic growth factors, within three weeks of beginning the trial, and should have recovered from all toxicities of prior therapy (to
grade 0 or 1). - 7. ECOG performance status of ≤ 2 at study entry, or Karnofsky ≥ 60%.
- 8. Laboratory test results within these ranges:
- a. Calculated creatinine clearance by MDRD (CrCL) >50 ml/min/1.73 squared meter
- b. Total bilirubin ≤ 2.0 mg/dL unless due to Gilbert’s syndrome, hemolysis, or ineffective hematopoiesis AST (SGOT) and ALT (SGPT) ≤ 3 × ULN
- 9. Females of childbearing potential must have negative pregnancy test.
- 10. Patients must have no clinical evidence of CNS or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia.
- 11. Patients must have no serious or uncontrolled medical conditions.
- Eligibility criteria - dose expansion. This phase will recruit patients with relapsed/refractory AML (cohort 1) and patients with HR-MDS not responding to hypomethylating agents (cohort 2) and will follow the noted eligibility criteria above (aside from #5 above in MDS patients), including pathologically confirmed CMML or MDS with high risk features at the time of referral as defined by:
- 1. INT-2 or high IPSS score
- 2. Secondary MDS
- 3. INT-1 MDS with excess blasts (≥ 5% blasts in BM) or RBC or platelet transfusion-dependency
- 4. CMML with ≥ 5% marrow blasts, or RBC or platelet transfusion-dependency, abnormal karyotype, or proliferative features
- All HR-MDS patients are required to have failed or relapsed after an initial response to hypomethylating agents or have refused to receive hypomethylating therapy. Failure to respond is defined as failing to achieve a CR, PR or HI after at least 4 cycles of hypomethylating therapy.
- For the dose escalating phase, IRX5183 is administered orally in daily doses continually in 28 day cycles until toxicity or disease progression. Bone marrow testing during each of the first 4 cycles determines marrow status and response. Only patients with relapsed or refractory AML are enrolled in the dose escalation phase. The starting dose (DL1) of single agent IRX5183 is 30 mg/m2/day, and the individual dosing levels are noted below:
-
Dose level (DL) Daily dose (mg/m2) DL(-1) 15 DL1 30 DL2 45 DL3 60 DL4 75 - The phase-expansion part of the study uses the optimal dose identified in the phase-escalation part of the study and includes two separate arms; one for AML patients and another for HR-MDS, and each of these two arms will recruit 26 patients.
- Dose levels are explored according to a traditional 3+3 design, with an aim to enroll 3 subjects at a time to determine the toxicity profile of IRX5183 in AML patients. If none of the three patients receiving DL1 experiences a DLT, another three patients will be treated at the next higher dose level. However, if one of the first three patients experiences a DLT, three more patients will be treated at the same dose level. The dose escalation will continue until at least two patients among a cohort of 3-6 patients experience DLTs. If two or more patients experience DLT on DL1, the next patient will be recruited to DL(-1). The MTD of single agent IRX5183 will be the highest dose at which 0 or 1 DLT are seen in a cohort of six subjects.
- For the
phase 2 dose expansion cohort, patients with AML are continued to be enrolled at the MTD, with goal of enrolling 26 patients (inclusive of patients treated at the MTD in first phase of the trial). Patients continue on single agent IRX5183 until they experience toxicity or disease progression. If patients achieve a complete remission, they have the option to consolidate with transplant, chemotherapy, and/or continue on maintenance IRX5183. If patients achieve a partial response or hematologic improvement they have the option to obtain salvage therapy in combination with IRX5183. For MDS patients, thephase 2 dose expansion cohort will recruit 26 patients who receive single agent IRX5183 at the MTD from the first phase of the trial. They also continue until undue toxicity or disease progression. Patients who achieve hematologic improvement or better have the option to consolidate with transplant, combine with demethylating agent therapy, or continue on maintenance IRX5183. - Plasma concentrations of IRX5183 are evaluated for the escalation and expansion phases, targeting safe and effective retinoid levels by pharmacokinetics using LCM-MS (liquid chromatography-mass spectroscopy tandem). Targeting peak levels of 1 pM should avoid systemic toxicity, while presumably preserving local BM niche retinoid levels. The plasma concentration of IRX5183 are obtained using a single 2 mL blood sample, pre-dose on
day 14. Samples are shipped to and analyzed by the designated analytical laboratory. - In addition to assessing standard clinical response criteria, BM cellular (normal HSCs and LSCs) concentrations, peripheral blood and bone marrow blast counts, markers of differentiation, apoptosis, and clonogenic growth are determined. A bone marrow aspirate and biopsy are obtained at baseline, on
day 14, and at the end each of the first 4 cycles of therapy. Differentiation is assessed using flow cytometry, comparing expression of differentiation markers on CD45 positive cells and ALDHint LSCs onday 14 marrow versus baseline. FISH analysis is also conducted after each cycle for patients with baseline abnormalities to determine if leukemic clone still present onday 14. - Expected outcomes: Patients receiving RARα selective agonist are monitored for response criteria based on hematological parameters including complete blood counts and percentage of leukemia blasts in the peripheral blood and in the bone marrow. Patients with improved neutrophil count, decreased transfusion requirements of red blood cells and platelets together with decreased percentage of blasts in the bone marrow and induction of differentiation and apoptosis of these malignant blasts are deemed responsive to therapy. Quality of life parameters such as pain, performance status and participation in activity of daily living and instrumental activities of daily living are assessed to evaluate the impact of this therapy on study patients. Use of this RARα selective agonist is expected to improve hematological and quality of life parameters in patients with MDS/AML and solid malignancies. In addition, the use of the RARα agonist which is CYP26 resistant may result in differentiation and thus elimination of minimal residual disease in the bone marrow of these patients.
- The ultimate goal is to develop better treatments for patients with relapsed/refractory AML and this study will provide valuable insights into the use of novel retinoids in this setting.
- Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” As used herein the terms “about” and “approximately” means within 10 to 15%, preferably within 5 to 10%. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
- The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
- Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
- Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
- Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.
- Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above-cited references and printed publications are individually incorporated herein by reference in their entirety.
- In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.
Claims (12)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/308,961 US20230310354A1 (en) | 2015-11-25 | 2023-04-28 | Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562260098P | 2015-11-25 | 2015-11-25 | |
PCT/US2016/063659 WO2017091762A1 (en) | 2015-11-25 | 2016-11-23 | Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer |
US201815777868A | 2018-05-21 | 2018-05-21 | |
US17/136,428 US11648222B2 (en) | 2015-11-25 | 2020-12-29 | Use of CYP26-resistant RAR alpha selective agonists in the treatment of cancer |
US18/308,961 US20230310354A1 (en) | 2015-11-25 | 2023-04-28 | Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/136,428 Division US11648222B2 (en) | 2015-11-25 | 2020-12-29 | Use of CYP26-resistant RAR alpha selective agonists in the treatment of cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
US20230310354A1 true US20230310354A1 (en) | 2023-10-05 |
Family
ID=58763652
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/777,868 Active US10940127B2 (en) | 2015-11-25 | 2016-11-23 | Use of CYP26-resistant RAR alpha selective agonists in the treatment of cancer |
US17/135,238 Abandoned US20210137865A1 (en) | 2015-11-25 | 2020-12-28 | Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer |
US17/136,428 Active US11648222B2 (en) | 2015-11-25 | 2020-12-29 | Use of CYP26-resistant RAR alpha selective agonists in the treatment of cancer |
US17/685,661 Abandoned US20220184013A1 (en) | 2015-11-25 | 2022-03-03 | Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer |
US18/308,961 Pending US20230310354A1 (en) | 2015-11-25 | 2023-04-28 | Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/777,868 Active US10940127B2 (en) | 2015-11-25 | 2016-11-23 | Use of CYP26-resistant RAR alpha selective agonists in the treatment of cancer |
US17/135,238 Abandoned US20210137865A1 (en) | 2015-11-25 | 2020-12-28 | Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer |
US17/136,428 Active US11648222B2 (en) | 2015-11-25 | 2020-12-29 | Use of CYP26-resistant RAR alpha selective agonists in the treatment of cancer |
US17/685,661 Abandoned US20220184013A1 (en) | 2015-11-25 | 2022-03-03 | Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer |
Country Status (6)
Country | Link |
---|---|
US (5) | US10940127B2 (en) |
EP (3) | EP4098257A1 (en) |
DK (1) | DK3380086T3 (en) |
ES (1) | ES2898676T3 (en) |
PL (1) | PL3380086T3 (en) |
WO (1) | WO2017091762A1 (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014145295A1 (en) | 2013-03-15 | 2014-09-18 | Avisenna Cosmetics, Llc | Topical compositions for reducing aging effects |
PL3277272T3 (en) | 2015-03-31 | 2022-01-24 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-agonists |
EP4098257A1 (en) | 2015-11-25 | 2022-12-07 | IO Therapeutics, Inc. | Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer |
US9868994B2 (en) | 2016-04-08 | 2018-01-16 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-α agonists |
KR102457851B1 (en) * | 2016-04-08 | 2022-10-25 | 사이로스 파마수티컬스, 인크. | RARA agonists for the treatment of AML and MDS |
MX2020000467A (en) | 2017-07-13 | 2020-08-03 | Io Therapeutics Inc | Immunomodulatory retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy. |
KR20200044889A (en) | 2017-08-31 | 2020-04-29 | 아이오 테라퓨틱스, 인크. | RAR selective agonists in combination with immunomodulators for cancer immunotherapy |
EP4192443A1 (en) * | 2020-08-06 | 2023-06-14 | Syros Pharmaceuticals, Inc. | Therapies for treating aml and uses of rara agonists, hypomethylating agents, and bcl-2 inhibitors |
WO2024006732A1 (en) | 2022-06-27 | 2024-01-04 | Io Therapeutics, Inc. | Synthesis of tetrahydronaphthalenols and uses thereof |
CN115317515A (en) * | 2022-07-19 | 2022-11-11 | 沈阳药科大学 | Multi-effect synergetic biomimetic mineralized nano preparation of lonidamine/bovine serum albumin/iron phosphate and preparation method and application thereof |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1576007A (en) | 1976-02-11 | 1980-10-01 | Beecham Group Ltd | Hypolipidaemic compositions |
US4326055A (en) | 1977-12-22 | 1982-04-20 | Hoffmann-La Roche Inc. | Stilbene derivatives |
US5234926A (en) | 1987-03-20 | 1993-08-10 | Allergan, Inc. | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
US5324840A (en) | 1992-06-11 | 1994-06-28 | Allergan, Inc. | Method of treatment with compounds having retinoid-like activity and reduced skin toxicity and lacking teratogenic effects |
CA2129846A1 (en) | 1992-12-28 | 1994-07-07 | Norimasa Miyamoto | Heterocyclic carbonic acid derivatives which bind to retinoid receptors (rar) |
US5455265A (en) | 1993-02-11 | 1995-10-03 | Allergan, Inc. | Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors |
CA2138000A1 (en) | 1994-01-03 | 1995-07-04 | John E. Starrett, Jr. | Retinoid-like compounds |
US5824685A (en) | 1995-02-01 | 1998-10-20 | The Johns Hopkins University School Of Medicine | Method of preventing proliferation of retinal pigment epithelium by retinoic acid receptor agonists |
US5958954A (en) | 1995-09-01 | 1999-09-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US5776699A (en) | 1995-09-01 | 1998-07-07 | Allergan, Inc. | Method of identifying negative hormone and/or antagonist activities |
US6942980B1 (en) | 1995-09-01 | 2005-09-13 | Allergan, Inc. | Methods of identifying compounds having nuclear receptor negative hormone and/or antagonist activities |
FR2739557B1 (en) | 1995-10-09 | 1997-11-14 | Cird Galderma | USE OF A RAR-GAMMA SPECIFIC AGONIST LIGAND |
US5965606A (en) * | 1995-12-29 | 1999-10-12 | Allergan Sales, Inc. | Methods of treatment with compounds having RAR.sub.α receptor specific or selective activity |
US5877207A (en) | 1996-03-11 | 1999-03-02 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US5723666A (en) | 1996-06-21 | 1998-03-03 | Allergan | Oxime substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
JP2001500486A (en) | 1996-08-28 | 2001-01-16 | アンスティテュ ナショナル デゥ ラ サンテ エ デゥ ラ ルシェルシュ メディカル | Therapeutic combinations of RAR antagonists and RXR agonists and uses thereof |
US5739338A (en) | 1996-11-05 | 1998-04-14 | Allergan | N-aryl substituted tetrahydroquinolines having retinoid agonist, retinoid antagonist or retinoid inverse agonist type biological activity |
US6037488A (en) | 1997-04-19 | 2000-03-14 | Allergan Sales, Inc. | Trisubstituted phenyl derivatives having retinoid agonist, antagonist or inverse agonist type biological activity |
US5919970A (en) | 1997-04-24 | 1999-07-06 | Allergan Sales, Inc. | Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity |
CA2375797A1 (en) | 1999-06-11 | 2000-12-21 | Allergan Sales, Inc. | Organosilyl compounds having nuclear hormone receptor modulating activity |
AU6228000A (en) | 1999-07-23 | 2001-02-13 | Allergan Sales, Inc. | The use of retinoid receptor antagonists in the treatment of prostate carcinoma |
TWI281911B (en) | 2000-04-04 | 2007-06-01 | Allergan Inc | Treatment of tumors with RARalpha selective retinoid compounds in combination with other anti-tumor agents |
JP4118675B2 (en) | 2000-10-02 | 2008-07-16 | エフ.ホフマン−ラ ロシュ アーゲー | A new retinoid for the treatment of emphysema |
US7429596B2 (en) | 2003-06-20 | 2008-09-30 | The Regents Of The University Of California | 1H-pyrrolo [2,3-D] pyrimidine derivatives and methods of use thereof |
WO2005046726A2 (en) | 2003-11-12 | 2005-05-26 | Allergan, Inc. | Combinations for inhibiting cell growth which contains an inhibitor of human ck1 alpha activity and a rxr agonist |
CA2550010A1 (en) | 2003-12-17 | 2005-06-30 | Allergan, Inc. | Methods for treating retinoid responsive disorders using selective inhibitors of cyp26a and cyp26b |
US7476673B2 (en) | 2003-12-30 | 2009-01-13 | Allergan, Inc. | Disubstituted chalcone oximes as selective agonists of RARγ retinoid receptors |
WO2006030442A2 (en) | 2004-09-16 | 2006-03-23 | Gamida-Cell Ltd. | Methods of ex vivo progenitor and stem cell expansion by co-culture with mesenchymal cells |
ES2690304T3 (en) | 2005-09-30 | 2018-11-20 | Io Therapeutics, Llc | Cancer treatment with specific RXR agonists |
CA2651487A1 (en) | 2006-05-16 | 2007-11-29 | Vitae Pharmaceuticals, Inc. | Methods for treating chemotherapy and radiation therapy side effects |
JP2009542608A (en) | 2006-06-29 | 2009-12-03 | アステックス・セラピューティクス・リミテッド | Pharmaceutical combination |
WO2008034074A2 (en) | 2006-09-15 | 2008-03-20 | The Johns Hopkins University | Cyclosphosphamide in combination with anti-idiotypic vaccines |
AU2008209555A1 (en) * | 2007-01-23 | 2008-07-31 | Gloucester Pharmaceuticals, Inc. | Combination therapy comprising romidepsin and I.A. bortezomib |
WO2008121570A1 (en) | 2007-03-29 | 2008-10-09 | Irm Llc | Compounds and methods for modulating g protein-coupled receptors |
ES2559420T3 (en) * | 2007-03-30 | 2016-02-12 | Tmrc Co., Ltd. | Tamibarotene capsule preparation |
WO2009147169A1 (en) * | 2008-06-03 | 2009-12-10 | Universite Paris Diderot-Paris 7 | Pharmaceuticl compositions useful for the treatment of cancers, in particular acute myeloid leukemia and acute promyelocytic leukemia |
AU2009314512B2 (en) * | 2008-11-17 | 2013-04-04 | Dr. Reddy's Laboratories Ltd. | Lenalidomide solvates and processes |
WO2010099601A1 (en) * | 2009-03-05 | 2010-09-10 | University Health Network | Use of 5ahq and bortezomib for the treatment of hematological diseases |
WO2012079022A1 (en) | 2010-12-10 | 2012-06-14 | Concert Pharmaceuticals, Inc. | Substituted dioxopiperidinyl phthalimide derivatives |
CN103702967A (en) | 2011-03-14 | 2014-04-02 | 貝丝以色列女执事医疗中心 | Methods and compositions for treatment of proliferative disorders |
AU2014369446C1 (en) | 2013-12-20 | 2020-03-12 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
WO2015157125A1 (en) | 2014-04-11 | 2015-10-15 | The University Of North Carolina At Chapel Hill | Therapuetic uses of selected pyrazolopyrimidine compounds with anti-mer tyrosine kinase activity |
EP3238744A4 (en) | 2014-12-25 | 2018-09-26 | International Institute of Cancer Immunology, Inc. | Method for modifying t cell population |
JP2018512396A (en) | 2015-03-09 | 2018-05-17 | キングス・カレッジ・ロンドン | Combination therapy with RAR alpha agonists to enhance TH1 response |
US9839687B2 (en) * | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
EP4098257A1 (en) | 2015-11-25 | 2022-12-07 | IO Therapeutics, Inc. | Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer |
US9868994B2 (en) * | 2016-04-08 | 2018-01-16 | Syros Pharmaceuticals, Inc. | Methods of stratifying patients for treatment with retinoic acid receptor-α agonists |
CN109310763B (en) | 2016-06-10 | 2022-10-21 | Io治疗公司 | Receptor selective retinoid and rexinoid compounds and immunomodulators for cancer immunotherapy |
MX2020000467A (en) | 2017-07-13 | 2020-08-03 | Io Therapeutics Inc | Immunomodulatory retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy. |
-
2016
- 2016-11-23 EP EP22186761.7A patent/EP4098257A1/en not_active Withdrawn
- 2016-11-23 US US15/777,868 patent/US10940127B2/en active Active
- 2016-11-23 EP EP21201920.2A patent/EP3957304A1/en active Pending
- 2016-11-23 PL PL16869301T patent/PL3380086T3/en unknown
- 2016-11-23 DK DK16869301.8T patent/DK3380086T3/en active
- 2016-11-23 EP EP16869301.8A patent/EP3380086B1/en active Active
- 2016-11-23 ES ES16869301T patent/ES2898676T3/en active Active
- 2016-11-23 WO PCT/US2016/063659 patent/WO2017091762A1/en active Application Filing
-
2020
- 2020-12-28 US US17/135,238 patent/US20210137865A1/en not_active Abandoned
- 2020-12-29 US US17/136,428 patent/US11648222B2/en active Active
-
2022
- 2022-03-03 US US17/685,661 patent/US20220184013A1/en not_active Abandoned
-
2023
- 2023-04-28 US US18/308,961 patent/US20230310354A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
DK3380086T3 (en) | 2021-11-22 |
EP4098257A1 (en) | 2022-12-07 |
US20180333380A1 (en) | 2018-11-22 |
US20220184013A1 (en) | 2022-06-16 |
EP3380086A4 (en) | 2019-12-04 |
PL3380086T3 (en) | 2022-02-21 |
US11648222B2 (en) | 2023-05-16 |
EP3957304A1 (en) | 2022-02-23 |
EP3380086B1 (en) | 2021-10-13 |
WO2017091762A1 (en) | 2017-06-01 |
US20210137866A1 (en) | 2021-05-13 |
EP3380086A1 (en) | 2018-10-03 |
US20210137865A1 (en) | 2021-05-13 |
ES2898676T3 (en) | 2022-03-08 |
US10940127B2 (en) | 2021-03-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11648222B2 (en) | Use of CYP26-resistant RAR alpha selective agonists in the treatment of cancer | |
US10973788B2 (en) | Treatment of cancer with specific RXR agonists | |
JP6727237B2 (en) | Combination therapy for the treatment of hematological cancers and solid tumors | |
US20040072824A1 (en) | Methods and compositions for the treatment of cancer | |
WO2012050374A2 (en) | Immunotherapy for solid tumors | |
US7893045B2 (en) | Methods for treating lymphomas in certain patient populations and screening patients for said therapy | |
US20210000845A1 (en) | Methods of treating cancer in pediatric patients | |
WO2018156680A1 (en) | Treatment of refractory of relapsed hematological cancer with durvalumab | |
WO2007143096A2 (en) | Compounds for treating cancers |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: THE JOHNS HOPKINS UNIVERSITY, MARYLAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GHIAUR, GABRIEL;JONES, RICHARD J.;ALONSO, SALVADOR;REEL/FRAME:063493/0226 Effective date: 20180502 Owner name: IO THERAPEUTICS, INC., TEXAS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CHANDRARATNA, ROSHANTHA A.;REEL/FRAME:063493/0134 Effective date: 20180309 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |