AU2006208012B2 - Treatment of metastasized tumors - Google Patents
Treatment of metastasized tumors Download PDFInfo
- Publication number
- AU2006208012B2 AU2006208012B2 AU2006208012A AU2006208012A AU2006208012B2 AU 2006208012 B2 AU2006208012 B2 AU 2006208012B2 AU 2006208012 A AU2006208012 A AU 2006208012A AU 2006208012 A AU2006208012 A AU 2006208012A AU 2006208012 B2 AU2006208012 B2 AU 2006208012B2
- Authority
- AU
- Australia
- Prior art keywords
- cancer
- compound
- tumor
- subject
- tautomer
- 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.)
- Ceased
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 227
- 238000011282 treatment Methods 0.000 title claims description 79
- 150000001875 compounds Chemical class 0.000 claims abstract description 195
- 238000000034 method Methods 0.000 claims abstract description 78
- 239000000203 mixture Substances 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 54
- 239000003814 drug Substances 0.000 claims abstract description 38
- 208000037819 metastatic cancer Diseases 0.000 claims abstract description 15
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 76
- 208000034578 Multiple myelomas Diseases 0.000 claims description 44
- 206010060862 Prostate cancer Diseases 0.000 claims description 42
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 42
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 35
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 35
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 claims description 24
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 claims description 24
- 210000000988 bone and bone Anatomy 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 230000012010 growth Effects 0.000 claims description 16
- 201000005787 hematologic cancer Diseases 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 206010005003 Bladder cancer Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 206010014733 Endometrial cancer Diseases 0.000 claims description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 5
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 5
- 208000034951 Genetic Translocation Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 claims description 5
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
- 201000005188 adrenal gland cancer Diseases 0.000 claims description 5
- 208000024447 adrenal gland neoplasm Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 5
- 208000005017 glioblastoma Diseases 0.000 claims description 5
- 201000010536 head and neck cancer Diseases 0.000 claims description 5
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 201000002628 peritoneum cancer Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 5
- 229940122361 Bisphosphonate Drugs 0.000 claims description 4
- 208000001132 Osteoporosis Diseases 0.000 claims description 4
- 150000004663 bisphosphonates Chemical group 0.000 claims description 4
- 150000003893 lactate salts Chemical class 0.000 claims description 4
- 206010005949 Bone cancer Diseases 0.000 claims 4
- 208000018084 Bone neoplasm Diseases 0.000 claims 4
- 230000017066 negative regulation of growth Effects 0.000 claims 1
- 229960005486 vaccine Drugs 0.000 claims 1
- -1 tautomer Chemical class 0.000 abstract description 18
- 208000011575 metastatic malignant neoplasm Diseases 0.000 abstract description 10
- 210000004027 cell Anatomy 0.000 description 140
- 229940125904 compound 1 Drugs 0.000 description 86
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 84
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 81
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 78
- 238000006243 chemical reaction Methods 0.000 description 72
- 241000699670 Mus sp. Species 0.000 description 70
- 239000003981 vehicle Substances 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- 201000011510 cancer Diseases 0.000 description 46
- 230000005764 inhibitory process Effects 0.000 description 46
- 230000000694 effects Effects 0.000 description 42
- 210000004369 blood Anatomy 0.000 description 36
- 239000008280 blood Substances 0.000 description 36
- 201000000050 myeloid neoplasm Diseases 0.000 description 32
- 210000001185 bone marrow Anatomy 0.000 description 31
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 30
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 30
- 108091000080 Phosphotransferase Proteins 0.000 description 29
- 102000020233 phosphotransferase Human genes 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- PIQCTGMSNWUMAF-UHFFFAOYSA-N chembl522892 Chemical compound C1CN(C)CCN1C1=CC=C(NC(=N2)C=3C(NC4=CC=CC(F)=C4C=3N)=O)C2=C1 PIQCTGMSNWUMAF-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 108090000765 processed proteins & peptides Proteins 0.000 description 23
- 238000001727 in vivo Methods 0.000 description 22
- 230000004083 survival effect Effects 0.000 description 22
- 239000002904 solvent Substances 0.000 description 21
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 239000008194 pharmaceutical composition Substances 0.000 description 20
- 210000004881 tumor cell Anatomy 0.000 description 20
- 101150086096 Eif2ak3 gene Proteins 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 17
- 230000004614 tumor growth Effects 0.000 description 17
- 102000001712 STAT5 Transcription Factor Human genes 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 230000035755 proliferation Effects 0.000 description 16
- 230000004044 response Effects 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 108010029477 STAT5 Transcription Factor Proteins 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 102000005962 receptors Human genes 0.000 description 15
- 108020003175 receptors Proteins 0.000 description 15
- 239000000758 substrate Substances 0.000 description 15
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 230000035772 mutation Effects 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 230000003389 potentiating effect Effects 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 210000001519 tissue Anatomy 0.000 description 14
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 13
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 238000006366 phosphorylation reaction Methods 0.000 description 13
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 12
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 12
- 230000026731 phosphorylation Effects 0.000 description 12
- 239000000523 sample Substances 0.000 description 12
- 238000007920 subcutaneous administration Methods 0.000 description 12
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 238000011161 development Methods 0.000 description 11
- 230000018109 developmental process Effects 0.000 description 11
- 238000004821 distillation Methods 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 239000007789 gas Substances 0.000 description 11
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 11
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 10
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 230000033115 angiogenesis Effects 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 9
- 108700020796 Oncogene Proteins 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 231100000673 dose–response relationship Toxicity 0.000 description 9
- 238000011156 evaluation Methods 0.000 description 9
- 238000003384 imaging method Methods 0.000 description 9
- 238000011081 inoculation Methods 0.000 description 9
- 208000032839 leukemia Diseases 0.000 description 9
- 230000001394 metastastic effect Effects 0.000 description 9
- 206010061289 metastatic neoplasm Diseases 0.000 description 9
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 239000011535 reaction buffer Substances 0.000 description 9
- 230000011664 signaling Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 206010006187 Breast cancer Diseases 0.000 description 8
- 208000026310 Breast neoplasm Diseases 0.000 description 8
- 241000699660 Mus musculus Species 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 8
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 8
- 230000003247 decreasing effect Effects 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 238000011580 nude mouse model Methods 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- MWLBMGPQZJDFKZ-UHFFFAOYSA-N 23491-48-7 Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(N)=C1 MWLBMGPQZJDFKZ-UHFFFAOYSA-N 0.000 description 7
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 7
- 206010027476 Metastases Diseases 0.000 description 7
- 206010027458 Metastases to lung Diseases 0.000 description 7
- 229930012538 Paclitaxel Natural products 0.000 description 7
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 7
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 7
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 7
- 241000021375 Xenogenes Species 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 108700014844 flt3 ligand Proteins 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 230000003902 lesion Effects 0.000 description 7
- 239000002207 metabolite Substances 0.000 description 7
- 229960001592 paclitaxel Drugs 0.000 description 7
- 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 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 6
- ZCWXYZBQDNFULS-UHFFFAOYSA-N 5-chloro-2-nitroaniline Chemical compound NC1=CC(Cl)=CC=C1[N+]([O-])=O ZCWXYZBQDNFULS-UHFFFAOYSA-N 0.000 description 6
- 229910052693 Europium Inorganic materials 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 6
- 101000851030 Homo sapiens Vascular endothelial growth factor receptor 3 Proteins 0.000 description 6
- 102000043136 MAP kinase family Human genes 0.000 description 6
- 108091054455 MAP kinase family Proteins 0.000 description 6
- 206010027457 Metastases to liver Diseases 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 101710151245 Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 6
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 108010090804 Streptavidin Proteins 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- 230000005754 cellular signaling Effects 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 6
- 239000012091 fetal bovine serum Substances 0.000 description 6
- 229940126864 fibroblast growth factor Drugs 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000000021 kinase assay Methods 0.000 description 6
- 208000014018 liver neoplasm Diseases 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- FSPQCTGGIANIJZ-UHFFFAOYSA-N 2-[[(3,4-dimethoxyphenyl)-oxomethyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=C(C(N)=O)C(CCCC2)=C2S1 FSPQCTGGIANIJZ-UHFFFAOYSA-N 0.000 description 5
- 102000003952 Caspase 3 Human genes 0.000 description 5
- 108090000397 Caspase 3 Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 5
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 5
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 5
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 5
- 108091008605 VEGF receptors Proteins 0.000 description 5
- 238000010171 animal model Methods 0.000 description 5
- 229940041181 antineoplastic drug Drugs 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000012417 linear regression Methods 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 201000005202 lung cancer Diseases 0.000 description 5
- 208000020816 lung neoplasm Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000009401 metastasis Effects 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 230000003285 pharmacodynamic effect Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 230000005945 translocation Effects 0.000 description 5
- 210000000689 upper leg Anatomy 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- IQUNZGOZUJITBJ-UHFFFAOYSA-N 2-amino-6-fluorobenzonitrile Chemical compound NC1=CC=CC(F)=C1C#N IQUNZGOZUJITBJ-UHFFFAOYSA-N 0.000 description 4
- 101150012716 CDK1 gene Proteins 0.000 description 4
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 4
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 4
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 4
- 241000283984 Rodentia Species 0.000 description 4
- 230000001028 anti-proliverative effect Effects 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000003364 immunohistochemistry Methods 0.000 description 4
- 239000004310 lactic acid Substances 0.000 description 4
- 235000014655 lactic acid Nutrition 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 239000012188 paraffin wax Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 3
- SHBHYINHXNTBRP-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-methylsulfonylethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCS(=O)(=O)C)C=CC=1 SHBHYINHXNTBRP-UHFFFAOYSA-N 0.000 description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 108091008794 FGF receptors Proteins 0.000 description 3
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 3
- 241000238631 Hexapoda Species 0.000 description 3
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000000719 MTS assay Methods 0.000 description 3
- 231100000070 MTS assay Toxicity 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 101150038994 PDGFRA gene Proteins 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 3
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000001446 anti-myeloma Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000003305 autocrine Effects 0.000 description 3
- 230000035578 autophosphorylation Effects 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 101150073031 cdk2 gene Proteins 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000007783 downstream signaling Effects 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 208000010726 hind limb paralysis Diseases 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 210000004373 mandible Anatomy 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 238000010837 poor prognosis Methods 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000013207 serial dilution Methods 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- 241000701447 unidentified baculovirus Species 0.000 description 3
- 230000006711 vascular endothelial growth factor production Effects 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- HDHQZCHIXUUSMK-UHFFFAOYSA-N 4-hydroxy-2-quinolone Chemical compound C1=CC=C2C(O)=CC(=O)NC2=C1 HDHQZCHIXUUSMK-UHFFFAOYSA-N 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 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 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 206010019695 Hepatic neoplasm Diseases 0.000 description 2
- 102100029234 Histone-lysine N-methyltransferase NSD2 Human genes 0.000 description 2
- 101710196680 Histone-lysine N-methyltransferase NSD2 Proteins 0.000 description 2
- 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 2
- 101000823316 Homo sapiens Tyrosine-protein kinase ABL1 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 238000003109 Karl Fischer titration Methods 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 2
- 206010029113 Neovascularisation Diseases 0.000 description 2
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 101710121440 Proteinase-activated receptor 1 Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102100033643 Ribosomal protein S6 kinase alpha-3 Human genes 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102100022596 Tyrosine-protein kinase ABL1 Human genes 0.000 description 2
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 2
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000002730 additional effect Effects 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 230000009833 antibody interaction Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- YXCWBNCDJZEBKY-UHFFFAOYSA-N chembl377345 Chemical compound O=C1NC2=CC=CC=C2C(O)=C1C1=NC2=CC=CC=C2N1 YXCWBNCDJZEBKY-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000000326 densiometry Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- 238000001378 electrochemiluminescence detection Methods 0.000 description 2
- 210000002257 embryonic structure Anatomy 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- HYMXUYQKXCHWDC-UHFFFAOYSA-N ethyl 3-ethoxy-3-iminopropanoate;hydrochloride Chemical compound Cl.CCOC(=N)CC(=O)OCC HYMXUYQKXCHWDC-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000004077 genetic alteration Effects 0.000 description 2
- 231100000118 genetic alteration Toxicity 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000007925 intracardiac injection Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 210000002414 leg Anatomy 0.000 description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 230000000869 mutational effect Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- 238000003305 oral gavage Methods 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 210000004197 pelvis Anatomy 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 210000004180 plasmocyte Anatomy 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 210000003625 skull Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000001131 transforming effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- HBZBAMXERPYTFS-SECBINFHSA-N (4S)-2-(6,7-dihydro-5H-pyrrolo[3,2-f][1,3]benzothiazol-2-yl)-4,5-dihydro-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)[C@H]1CSC(=N1)c1nc2cc3CCNc3cc2s1 HBZBAMXERPYTFS-SECBINFHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- GBTVCCZNQCRKBW-UHFFFAOYSA-N 1h-benzimidazole;1h-quinolin-2-one Chemical class C1=CC=C2NC=NC2=C1.C1=CC=C2NC(=O)C=CC2=C1 GBTVCCZNQCRKBW-UHFFFAOYSA-N 0.000 description 1
- OZZQHCBFUVFZGT-UHFFFAOYSA-N 2-(2-hydroxypropanoyloxy)propanoic acid Chemical compound CC(O)C(=O)OC(C)C(O)=O OZZQHCBFUVFZGT-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DRUNJGIEUWMQHG-UHFFFAOYSA-N 4-amino-5-fluoro-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-quinolin-2-one Chemical compound O=C1NC2=CC=CC(F)=C2C(N)=C1C(NC1=CC=2)=NC1=CC=2N1CCNCC1 DRUNJGIEUWMQHG-UHFFFAOYSA-N 0.000 description 1
- VZYYJCUSXWDKJQ-UHFFFAOYSA-N 4-amino-5-fluoro-3-[6-(4-methyl-4-oxidopiperazin-4-ium-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one Chemical compound C1C[N+](C)([O-])CCN1C1=CC=C(NC(=N2)C=3C(NC4=CC=CC(F)=C4C=3N)=O)C2=C1 VZYYJCUSXWDKJQ-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 150000004331 4-hydroxyquinolines Chemical class 0.000 description 1
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WRDABNWSWOHGMS-UHFFFAOYSA-N AEBSF hydrochloride Chemical compound Cl.NCCC1=CC=C(S(F)(=O)=O)C=C1 WRDABNWSWOHGMS-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 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 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 1
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 1
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 1
- 102100022014 Angiopoietin-1 receptor Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000012526 B-cell neoplasm Diseases 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 206010061728 Bone lesion Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- 101150050673 CHK1 gene Proteins 0.000 description 1
- 101100439046 Caenorhabditis elegans cdk-2 gene Proteins 0.000 description 1
- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241001466804 Carnivora Species 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000008122 Casein Kinase I Human genes 0.000 description 1
- 108010049812 Casein Kinase I Proteins 0.000 description 1
- 102000011632 Caseins Human genes 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108010019244 Checkpoint Kinase 1 Proteins 0.000 description 1
- 102000006459 Checkpoint Kinase 1 Human genes 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 101150073133 Cpt1a gene Proteins 0.000 description 1
- 108010068192 Cyclin A Proteins 0.000 description 1
- 102000002427 Cyclin B Human genes 0.000 description 1
- 108010068150 Cyclin B Proteins 0.000 description 1
- 102000006311 Cyclin D1 Human genes 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 108010058545 Cyclin D3 Proteins 0.000 description 1
- 102100025191 Cyclin-A2 Human genes 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 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 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 101000827763 Drosophila melanogaster Fibroblast growth factor receptor homolog 1 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 1
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 1
- 102000054300 EC 2.7.11.- Human genes 0.000 description 1
- 108700035490 EC 2.7.11.- Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 101000600890 Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139) G2-specific protein kinase nimA Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 108010055196 EphA2 Receptor Proteins 0.000 description 1
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 206010063560 Excessive granulation tissue Diseases 0.000 description 1
- 101150009958 FLT4 gene Proteins 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 101150048336 Flt1 gene Proteins 0.000 description 1
- 102100037859 G1/S-specific cyclin-D3 Human genes 0.000 description 1
- 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 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 108010054422 HI peptide Proteins 0.000 description 1
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 1
- 108010075704 HLA-A Antigens Proteins 0.000 description 1
- 206010066476 Haematological malignancy Diseases 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000753291 Homo sapiens Angiopoietin-1 receptor Proteins 0.000 description 1
- 101100066427 Homo sapiens FCGR1A gene Proteins 0.000 description 1
- 101100335080 Homo sapiens FLT3 gene Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101100534458 Homo sapiens STAT5A gene Proteins 0.000 description 1
- 101001047681 Homo sapiens Tyrosine-protein kinase Lck Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 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 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102100039064 Interleukin-3 Human genes 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 1
- 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 1
- 241000288903 Lemuridae Species 0.000 description 1
- 241000283960 Leporidae Species 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 101150022636 MAFB gene Proteins 0.000 description 1
- 229940124647 MEK inhibitor Drugs 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 101710150918 Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 241000289419 Metatheria Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 108700027649 Mitogen-Activated Protein Kinase 3 Proteins 0.000 description 1
- 102100024192 Mitogen-activated protein kinase 3 Human genes 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000012124 Opti-MEM Substances 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 102000007987 Proto-Oncogene Proteins c-maf Human genes 0.000 description 1
- 108010089507 Proto-Oncogene Proteins c-maf Proteins 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 101710119204 Ribosomal protein S6 kinase alpha-3 Proteins 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 108010026479 Src peptide Proteins 0.000 description 1
- 108010039445 Stem Cell Factor Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 241000282887 Suidae Species 0.000 description 1
- 108010006830 TIE receptors Proteins 0.000 description 1
- 102000005450 TIE receptors Human genes 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 102100024036 Tyrosine-protein kinase Lck Human genes 0.000 description 1
- 102000016548 Vascular Endothelial Growth Factor Receptor-1 Human genes 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 101150045355 akt1 gene Proteins 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000003208 anti-thyroid effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940043671 antithyroid preparations Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 239000007900 aqueous suspension 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
- 229910052786 argon Inorganic materials 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 230000001908 autoinhibitory effect Effects 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- GHRQXJHBXKYCLZ-UHFFFAOYSA-L beta-glycerolphosphate Chemical compound [Na+].[Na+].CC(CO)OOP([O-])([O-])=O GHRQXJHBXKYCLZ-UHFFFAOYSA-L 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 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 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229950004271 brostallicin Drugs 0.000 description 1
- RXOVOXFAAGIKDQ-UHFFFAOYSA-N brostallicin Chemical compound C1=C(C(=O)NCCN=C(N)N)N(C)C=C1NC(=O)C1=CC(NC(=O)C=2N(C=C(NC(=O)C=3N(C=C(NC(=O)C(Br)=C)C=3)C)C=2)C)=CN1C RXOVOXFAAGIKDQ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound 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
- 230000036952 cancer formation Effects 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 150000001893 coumarin derivatives Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000007822 cytometric assay Methods 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
- 230000007402 cytotoxic response Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 230000029211 developmental cell growth Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 230000009699 differential effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 230000003292 diminished effect Effects 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
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000005014 ectopic expression Effects 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- ZAKAONRTRWRIJT-UHFFFAOYSA-N ethyl 3-ethoxy-3-iminopropanoate Chemical compound CCOC(=N)CC(=O)OCC ZAKAONRTRWRIJT-UHFFFAOYSA-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
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000006277 exogenous ligand Substances 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007897 gelcap Substances 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000009395 genetic defect Effects 0.000 description 1
- 238000003205 genotyping method Methods 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 210000001126 granulation tissue Anatomy 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000013427 histology analysis Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 102000049850 human FLT3 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- PQPVPZTVJLXQAS-UHFFFAOYSA-N hydroxy-methyl-phenylsilicon Chemical compound C[Si](O)C1=CC=CC=C1 PQPVPZTVJLXQAS-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 230000003116 impacting effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 238000001325 log-rank test Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000006510 metastatic growth Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 229950010895 midostaurin Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000011242 molecular targeted therapy Methods 0.000 description 1
- ZDZOTLJHXYCWBA-BSEPLHNVSA-N molport-006-823-826 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-BSEPLHNVSA-N 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229940043363 multi-kinase inhibitor Drugs 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000012316 non-parametric ANOVA Methods 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000004650 oncogenic pathway Effects 0.000 description 1
- 230000005959 oncogenic signaling Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 230000000010 osteolytic effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 210000003668 pericyte Anatomy 0.000 description 1
- 229960002087 pertuzumab Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 108010036962 polypeptide 3 90kDa ribosomal protein S6 kinase Proteins 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 230000005195 poor health Effects 0.000 description 1
- 238000012809 post-inoculation Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 210000001948 pro-b lymphocyte Anatomy 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000005267 prostate cell Anatomy 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 108010065251 protein kinase modulator Proteins 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229940120975 revlimid Drugs 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- UXXQOJXBIDBUAC-UHFFFAOYSA-N tandutinib Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229940034915 thalomid Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000013414 tumor xenograft model Methods 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US64756805P | 2005-01-27 | 2005-01-27 | |
| US60/647,568 | 2005-01-27 | ||
| US66924505P | 2005-04-06 | 2005-04-06 | |
| US60/669,245 | 2005-04-06 | ||
| US72205305P | 2005-09-29 | 2005-09-29 | |
| US60/722,053 | 2005-09-29 | ||
| PCT/US2006/002979 WO2006081445A2 (en) | 2005-01-27 | 2006-01-27 | Treatment of metastasized tumors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2006208012A1 AU2006208012A1 (en) | 2006-08-03 |
| AU2006208012B2 true AU2006208012B2 (en) | 2011-08-04 |
Family
ID=36741085
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2006208012A Ceased AU2006208012B2 (en) | 2005-01-27 | 2006-01-27 | Treatment of metastasized tumors |
Country Status (22)
| Country | Link |
|---|---|
| US (2) | US20060183750A1 (enExample) |
| EP (2) | EP1845990B1 (enExample) |
| JP (2) | JP5371246B2 (enExample) |
| KR (1) | KR101387985B1 (enExample) |
| CN (1) | CN103893181A (enExample) |
| AT (1) | ATE526025T1 (enExample) |
| AU (1) | AU2006208012B2 (enExample) |
| BR (1) | BRPI0607285A2 (enExample) |
| CA (1) | CA2596084A1 (enExample) |
| CY (1) | CY1112570T1 (enExample) |
| DK (1) | DK1845990T3 (enExample) |
| ES (2) | ES2374570T3 (enExample) |
| IL (1) | IL184866A0 (enExample) |
| MA (1) | MA29266B1 (enExample) |
| MX (1) | MX2007009099A (enExample) |
| NO (1) | NO20074360L (enExample) |
| PL (2) | PL2301546T3 (enExample) |
| PT (2) | PT2301546E (enExample) |
| SG (1) | SG173317A1 (enExample) |
| SI (1) | SI2301546T1 (enExample) |
| TN (1) | TNSN07294A1 (enExample) |
| WO (1) | WO2006081445A2 (enExample) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2334641T3 (es) | 2000-09-01 | 2010-03-15 | Novartis Vaccines And Diagnostics, Inc. | Derivados aza heterociclicos y su uso terapeutico. |
| NZ524717A (en) | 2000-09-11 | 2004-09-24 | Chiron Corp | Quinolinone derivatives |
| CA2496164C (en) | 2002-08-23 | 2010-11-09 | Chiron Corporation | Benzimidazole quinolinones and uses thereof |
| PT1885187E (pt) * | 2005-05-13 | 2013-12-16 | Novartis Ag | Métodos para o tratamento de cancro resistente a fármacos |
| RU2425041C2 (ru) * | 2005-05-23 | 2011-07-27 | Новартис Аг | Кристаллические и другие формы солей, образованных из молочной кислоты и 4-амино-5-фтор-3-[6-(4-метилпиперазин-1-ил)-1н-бензимидазол-2-ил]-1н-хинолин-2-она |
| AR070924A1 (es) * | 2008-03-19 | 2010-05-12 | Novartis Ag | Formas cristalinas y dos formas solvatadas de sales del acido lactico de 4- amino -5- fluoro-3-(5-(4-metilpiperazin-1-il ) -1h- bencimidazol-2-il) quinolin -2-(1h) - ona |
| US20120064008A1 (en) * | 2009-05-20 | 2012-03-15 | Bruce Zetter | Compositions for the treatment of metastatic cancer and methods of use thereof |
| TR201819653T4 (tr) * | 2010-04-16 | 2019-01-21 | Novartis Ag | Karaciğer kanserinin tedavisinde kullanılmaya yönelik organik bileşik. |
| KR20140023358A (ko) * | 2011-05-19 | 2014-02-26 | 노파르티스 아게 | 선양 낭성 암종의 치료에 사용하기 위한 4-아미노-5-플루오로-3-[6-(4-메틸피페라진-1-일)-1h-벤즈이미다졸-2-일]-1h-퀴놀린-2-온 |
| MX2014009303A (es) * | 2012-01-31 | 2014-10-14 | Novartis Ag | Combinacion de un inhibidor de rtk con un anti-estrogeno y uso del mismo para el tratamiento de cancer. |
| CN109689649B (zh) * | 2016-07-14 | 2022-07-19 | 百时美施贵宝公司 | 经二环杂芳基取代的化合物 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004018419A2 (en) * | 2002-08-23 | 2004-03-04 | Chiron Corporation | Benzimidazole quinolinones and uses thereof |
| WO2004043389A2 (en) * | 2002-11-13 | 2004-05-27 | Chiron Corporation | Methods of treating cancer and related methods |
| AU2005216904A1 (en) * | 2004-02-20 | 2005-09-09 | Novartis Vaccines And Diagnostics, Inc. | Modulation of inflammatory and metastatic processes |
| US20050261307A1 (en) * | 2002-08-23 | 2005-11-24 | Chiron Corporation | Inhibition of FGFR3 and treatment of multiple myeloma |
Family Cites Families (39)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3663606A (en) * | 1966-06-21 | 1972-05-16 | Mitsui Toatsu Chemicals | Organic imino-compounds |
| DE2363459A1 (de) | 1973-12-20 | 1975-06-26 | Basf Ag | Neue fluoreszierende chinolinverbindungen |
| US4659657A (en) * | 1982-12-24 | 1987-04-21 | Bayer Aktiengesellschaft | Chromogenic and fluorogenic esters for photometric or fluorimetric determination of phosphatases or sulphatases |
| US5073492A (en) * | 1987-01-09 | 1991-12-17 | The Johns Hopkins University | Synergistic composition for endothelial cell growth |
| JPH0699497B2 (ja) | 1987-04-16 | 1994-12-07 | 富士写真フイルム株式会社 | 光重合性組成物 |
| DE3932953A1 (de) * | 1989-10-03 | 1991-04-11 | Boehringer Mannheim Gmbh | Neue 2-bicyclo-benzimidazole, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| GB9108547D0 (en) | 1991-04-22 | 1991-06-05 | Fujisawa Pharmaceutical Co | Quinoline derivatives |
| USRE37650E1 (en) * | 1991-05-10 | 2002-04-09 | Aventis Pharmacetical Products, Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
| US5480883A (en) * | 1991-05-10 | 1996-01-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
| US5710158A (en) * | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
| US5856115A (en) * | 1991-05-24 | 1999-01-05 | Fred Hutchinson Cancer Research Center | Assay for identification therapeutic agents |
| EP0627940B1 (en) * | 1992-03-05 | 2003-05-07 | Board of Regents, The University of Texas System | Use of immunoconjugates for the diagnosis and/or therapy of vascularized tumors |
| JP3142378B2 (ja) | 1992-06-22 | 2001-03-07 | ティーディーケイ株式会社 | 有機ｅｌ素子 |
| US5763441A (en) * | 1992-11-13 | 1998-06-09 | Sugen, Inc. | Compounds for the treatment of disorders related to vasculogenesis and/or angiogenesis |
| US5981569A (en) * | 1992-11-13 | 1999-11-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Substituted phenylacrylonitrile compounds and compositions thereof for the treatment of disease |
| US5792771A (en) * | 1992-11-13 | 1998-08-11 | Sugen, Inc. | Quinazoline compounds and compositions thereof for the treatment of disease |
| JPH0743896A (ja) | 1993-07-28 | 1995-02-14 | Toyobo Co Ltd | 光重合性組成物 |
| JPH0829973A (ja) | 1994-07-11 | 1996-02-02 | Toyobo Co Ltd | 光重合性組成物 |
| JP3441246B2 (ja) | 1995-06-07 | 2003-08-25 | 富士写真フイルム株式会社 | 光重合性組成物 |
| GB9624482D0 (en) * | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
| DE19610723A1 (de) | 1996-03-19 | 1997-09-25 | Bayer Ag | Elektrolumineszierende Anordnungen unter Verwendung von Blendsystemen |
| US5942385A (en) * | 1996-03-21 | 1999-08-24 | Sugen, Inc. | Method for molecular diagnosis of tumor angiogenesis and metastasis |
| WO1997048697A1 (en) * | 1996-06-19 | 1997-12-24 | Rhone-Poulenc Rorer Limited | Substituted azabicylic compounds and their use as inhibitors of the production of tnf and cyclic amp phosphodiesterase |
| BR9711805A (pt) | 1996-06-20 | 2002-01-15 | Regents The Univesity Of Texas | Compostos e métodos para providenciar preparações farmacologicamente ativas e uso dos mesmos |
| US6111110A (en) * | 1996-10-30 | 2000-08-29 | Eli Lilly And Company | Synthesis of benzo[f]quinolinones |
| WO2001028993A2 (en) | 1999-10-19 | 2001-04-26 | Merck & Co. Inc. | Tyrosine kinase inhibitors |
| EP1226136B1 (en) | 1999-10-19 | 2004-12-29 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| US6420382B2 (en) | 2000-02-25 | 2002-07-16 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| JP2003523390A (ja) | 2000-02-25 | 2003-08-05 | メルク エンド カムパニー インコーポレーテッド | チロシンキナーゼ阻害薬 |
| US6313138B1 (en) * | 2000-02-25 | 2001-11-06 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| EP1351946A2 (en) * | 2000-09-01 | 2003-10-15 | Icos Corporation | Materials and methods to potentiate cancer treatment |
| ES2334641T3 (es) | 2000-09-01 | 2010-03-15 | Novartis Vaccines And Diagnostics, Inc. | Derivados aza heterociclicos y su uso terapeutico. |
| US20030028018A1 (en) | 2000-09-11 | 2003-02-06 | Chiron Coporation | Quinolinone derivatives |
| NZ524717A (en) * | 2000-09-11 | 2004-09-24 | Chiron Corp | Quinolinone derivatives |
| JP2004536113A (ja) * | 2001-07-03 | 2004-12-02 | カイロン コーポレイション | チロシンキナーゼおよびセリン／スレオニンキナーゼのインヒビターとしてのインダゾールベンズイミダゾール化合物 |
| US6774327B1 (en) * | 2003-09-24 | 2004-08-10 | Agilent Technologies, Inc. | Hermetic seals for electronic components |
| KR101224410B1 (ko) * | 2003-11-07 | 2013-01-23 | 노바티스 백신즈 앤드 다이아그노스틱스 인코포레이티드 | 퀴놀리논 화합물을 합성하는 방법 |
| US20060261307A1 (en) * | 2005-05-18 | 2006-11-23 | Black D J | Water Activated Organic Scavenger |
| KR102639757B1 (ko) | 2017-01-09 | 2024-02-23 | 엘지이노텍 주식회사 | 카메라 모듈 및 이를 포함하는 광학기기 |
-
2006
- 2006-01-27 KR KR1020077019428A patent/KR101387985B1/ko not_active Expired - Fee Related
- 2006-01-27 CN CN201410121175.8A patent/CN103893181A/zh active Pending
- 2006-01-27 PT PT101867570T patent/PT2301546E/pt unknown
- 2006-01-27 US US11/342,257 patent/US20060183750A1/en not_active Abandoned
- 2006-01-27 DK DK06733986.1T patent/DK1845990T3/da active
- 2006-01-27 EP EP06733986A patent/EP1845990B1/en not_active Not-in-force
- 2006-01-27 PL PL10186757T patent/PL2301546T3/pl unknown
- 2006-01-27 PT PT06733986T patent/PT1845990E/pt unknown
- 2006-01-27 EP EP10186757.0A patent/EP2301546B1/en not_active Revoked
- 2006-01-27 ES ES06733986T patent/ES2374570T3/es active Active
- 2006-01-27 MX MX2007009099A patent/MX2007009099A/es not_active Application Discontinuation
- 2006-01-27 ES ES10186757.0T patent/ES2525670T3/es active Active
- 2006-01-27 PL PL06733986T patent/PL1845990T3/pl unknown
- 2006-01-27 BR BRPI0607285-2A patent/BRPI0607285A2/pt not_active IP Right Cessation
- 2006-01-27 JP JP2007553278A patent/JP5371246B2/ja not_active Expired - Fee Related
- 2006-01-27 SG SG2011046166A patent/SG173317A1/en unknown
- 2006-01-27 AU AU2006208012A patent/AU2006208012B2/en not_active Ceased
- 2006-01-27 CA CA002596084A patent/CA2596084A1/en not_active Abandoned
- 2006-01-27 WO PCT/US2006/002979 patent/WO2006081445A2/en not_active Ceased
- 2006-01-27 SI SI200631858T patent/SI2301546T1/sl unknown
- 2006-01-27 AT AT06733986T patent/ATE526025T1/de active
-
2007
- 2007-07-26 IL IL184866A patent/IL184866A0/en unknown
- 2007-07-27 TN TNP2007000294A patent/TNSN07294A1/en unknown
- 2007-08-23 MA MA30162A patent/MA29266B1/fr unknown
- 2007-08-27 NO NO20074360A patent/NO20074360L/no not_active Application Discontinuation
-
2009
- 2009-12-31 US US12/650,725 patent/US20100173873A1/en not_active Abandoned
-
2011
- 2011-12-06 CY CY20111101216T patent/CY1112570T1/el unknown
-
2013
- 2013-06-20 JP JP2013129277A patent/JP2013177464A/ja not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004018419A2 (en) * | 2002-08-23 | 2004-03-04 | Chiron Corporation | Benzimidazole quinolinones and uses thereof |
| US20040092535A1 (en) * | 2002-08-23 | 2004-05-13 | Chiron Corporation | Benzimidazole quinolinones and uses thereof |
| US20050261307A1 (en) * | 2002-08-23 | 2005-11-24 | Chiron Corporation | Inhibition of FGFR3 and treatment of multiple myeloma |
| WO2004043389A2 (en) * | 2002-11-13 | 2004-05-27 | Chiron Corporation | Methods of treating cancer and related methods |
| AU2005216904A1 (en) * | 2004-02-20 | 2005-09-09 | Novartis Vaccines And Diagnostics, Inc. | Modulation of inflammatory and metastatic processes |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20100173873A1 (en) | Treatment of metastasized tumors | |
| AU2008226582B2 (en) | Treatment of melanoma | |
| WO2005047244A2 (en) | Inhibition of fgfr3 and treatment of multiple myeloma | |
| JP2013173787A (ja) | 薬剤耐性癌の処置方法 | |
| HK1155664B (en) | Treatment of metastasized tumors | |
| CN101146538A (zh) | 转移瘤的治疗 | |
| HK1117047A (en) | Treatment of metastasized tumors | |
| HK1110477B (en) | Methods for treating drug resistant cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| DA2 | Applications for amendment section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE PRIORITY DETAILS TO READ 60/647,568 27 JAN 2005 US; 60/722,053 28 SEPT 2005 US AND 60/669,245 06 APR 2005 US. |
|
| DA3 | Amendments made section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE PRIORITY DETAILS TO READ 60/647,568 27 JAN 2005 US; 60/722,053 29 SEP 2005 US AND 60/669,245 06 APR 2005 US |
|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |