CA2414967C - Valproic acid and derivatives thereof as histone deacetylase inhibitors - Google Patents
Valproic acid and derivatives thereof as histone deacetylase inhibitors Download PDFInfo
- Publication number
- CA2414967C CA2414967C CA002414967A CA2414967A CA2414967C CA 2414967 C CA2414967 C CA 2414967C CA 002414967 A CA002414967 A CA 002414967A CA 2414967 A CA2414967 A CA 2414967A CA 2414967 C CA2414967 C CA 2414967C
- Authority
- CA
- Canada
- Prior art keywords
- cells
- vpa
- valproic acid
- compound
- cancer
- 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.)
- Expired - Fee Related
Links
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 224
- 229960000604 valproic acid Drugs 0.000 title claims abstract description 115
- 239000003276 histone deacetylase inhibitor Substances 0.000 title claims description 30
- 229940121372 histone deacetylase inhibitor Drugs 0.000 title claims description 18
- 102000003964 Histone deacetylase Human genes 0.000 claims abstract description 65
- 108090000353 Histone deacetylase Proteins 0.000 claims abstract description 65
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 108010033040 Histones Proteins 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 23
- 230000006698 induction Effects 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 4
- 210000001685 thyroid gland Anatomy 0.000 claims abstract description 3
- 230000004069 differentiation Effects 0.000 claims description 27
- 102000006947 Histones Human genes 0.000 claims description 21
- 230000002401 inhibitory effect Effects 0.000 claims description 18
- 206010006187 Breast cancer Diseases 0.000 claims description 12
- 208000026310 Breast neoplasm Diseases 0.000 claims description 12
- 206010009944 Colon cancer Diseases 0.000 claims description 10
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 10
- 230000027455 binding Effects 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 206010038389 Renal cancer Diseases 0.000 claims description 7
- 230000001419 dependent effect Effects 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 238000013518 transcription Methods 0.000 claims description 7
- 230000035897 transcription Effects 0.000 claims description 7
- 238000001262 western blot Methods 0.000 claims description 7
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 6
- 238000003556 assay Methods 0.000 claims description 6
- 230000009286 beneficial effect Effects 0.000 claims description 6
- 230000002255 enzymatic effect Effects 0.000 claims description 6
- 230000021736 acetylation Effects 0.000 claims description 5
- 238000006640 acetylation reaction Methods 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 230000001624 sedative effect Effects 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 108010038795 estrogen receptors Proteins 0.000 claims description 3
- 201000010536 head and neck cancer Diseases 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 108010044467 Isoenzymes Proteins 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 210000001072 colon Anatomy 0.000 claims description 2
- 102000015694 estrogen receptors Human genes 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 230000011199 transformed cell apoptotic process Effects 0.000 claims description 2
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 claims 9
- 230000000694 effects Effects 0.000 abstract description 39
- 206010028980 Neoplasm Diseases 0.000 abstract description 26
- 108090000623 proteins and genes Proteins 0.000 abstract description 22
- 239000003112 inhibitor Substances 0.000 abstract description 9
- 230000001225 therapeutic effect Effects 0.000 abstract description 5
- 208000032839 leukemia Diseases 0.000 abstract description 4
- 230000006195 histone acetylation Effects 0.000 abstract description 3
- 238000012216 screening Methods 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 141
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 24
- RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 description 21
- 230000004913 activation Effects 0.000 description 17
- 201000011510 cancer Diseases 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 11
- 102000040945 Transcription factor Human genes 0.000 description 11
- 108091023040 Transcription factor Proteins 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 108700008625 Reporter Genes Proteins 0.000 description 10
- 230000006907 apoptotic process Effects 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 230000024245 cell differentiation Effects 0.000 description 10
- 108020001507 fusion proteins Proteins 0.000 description 10
- 102000037865 fusion proteins Human genes 0.000 description 10
- 239000003446 ligand Substances 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 9
- 108010001515 Galectin 4 Proteins 0.000 description 9
- 102100039556 Galectin-4 Human genes 0.000 description 9
- 102100022935 Nuclear receptor corepressor 1 Human genes 0.000 description 9
- 101710153661 Nuclear receptor corepressor 1 Proteins 0.000 description 9
- 229930189037 Trapoxin Natural products 0.000 description 9
- 230000001413 cellular effect Effects 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 108010060597 trapoxin A Proteins 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 9
- 239000002028 Biomass Substances 0.000 description 8
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 102000008169 Co-Repressor Proteins Human genes 0.000 description 7
- 108010060434 Co-Repressor Proteins Proteins 0.000 description 7
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 7
- 239000001961 anticonvulsive agent Substances 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 102000003702 retinoic acid receptors Human genes 0.000 description 7
- 108090000064 retinoic acid receptors Proteins 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- -1 Mad-1 Proteins 0.000 description 6
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 6
- 208000006265 Renal cell carcinoma Diseases 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- 230000030833 cell death Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000010348 incorporation Methods 0.000 description 6
- 230000000877 morphologic effect Effects 0.000 description 6
- 102000006255 nuclear receptors Human genes 0.000 description 6
- 108020004017 nuclear receptors Proteins 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 208000001608 teratocarcinoma Diseases 0.000 description 6
- 230000003390 teratogenic effect Effects 0.000 description 6
- 230000002103 transcriptional effect Effects 0.000 description 6
- 206010043275 Teratogenicity Diseases 0.000 description 5
- 102100022972 Transcription factor AP-2-alpha Human genes 0.000 description 5
- 101710189834 Transcription factor AP-2-alpha Proteins 0.000 description 5
- 230000004075 alteration Effects 0.000 description 5
- 230000025084 cell cycle arrest Effects 0.000 description 5
- 108010087914 epidermal growth factor receptor VIII Proteins 0.000 description 5
- 108020001756 ligand binding domains Proteins 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 201000010174 renal carcinoma Diseases 0.000 description 5
- 231100000378 teratogenic Toxicity 0.000 description 5
- 231100000211 teratogenicity Toxicity 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229940104230 thymidine Drugs 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 4
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 4
- 102000003893 Histone acetyltransferases Human genes 0.000 description 4
- 108090000246 Histone acetyltransferases Proteins 0.000 description 4
- 102000006601 Thymidine Kinase Human genes 0.000 description 4
- 108020004440 Thymidine kinase Proteins 0.000 description 4
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- 230000003556 anti-epileptic effect Effects 0.000 description 4
- 201000008275 breast carcinoma Diseases 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000007824 enzymatic assay Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 229940011871 estrogen Drugs 0.000 description 4
- 239000000262 estrogen Substances 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000005567 liquid scintillation counting Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 4
- 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 4
- 239000000758 substrate Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 239000005495 thyroid hormone Substances 0.000 description 4
- 229940036555 thyroid hormone Drugs 0.000 description 4
- 102000004217 thyroid hormone receptors Human genes 0.000 description 4
- 108090000721 thyroid hormone receptors Proteins 0.000 description 4
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 3
- XZFRIPGNUQRGPI-WBQKLGIQSA-N Carbaprostacyclin Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 XZFRIPGNUQRGPI-WBQKLGIQSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 108010077544 Chromatin Proteins 0.000 description 3
- 230000004568 DNA-binding Effects 0.000 description 3
- 108060006698 EGF receptor Proteins 0.000 description 3
- 102000001301 EGF receptor Human genes 0.000 description 3
- 101001095089 Homo sapiens PML-RARA-regulated adapter molecule 1 Proteins 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 102100022883 Nuclear receptor coactivator 3 Human genes 0.000 description 3
- 102100037019 PML-RARA-regulated adapter molecule 1 Human genes 0.000 description 3
- 230000001594 aberrant effect Effects 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
- 210000003483 chromatin Anatomy 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 230000009089 cytolysis Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000009396 hybridization Methods 0.000 description 3
- 239000012133 immunoprecipitate Substances 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000009456 molecular mechanism Effects 0.000 description 3
- 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 3
- 239000013642 negative control Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229920002401 polyacrylamide Polymers 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229930002330 retinoic acid Natural products 0.000 description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 229960001727 tretinoin Drugs 0.000 description 3
- 230000035899 viability Effects 0.000 description 3
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 108090000672 Annexin A5 Proteins 0.000 description 2
- 102000004121 Annexin A5 Human genes 0.000 description 2
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 206010019851 Hepatotoxicity Diseases 0.000 description 2
- 241000282412 Homo Species 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
- 229930193140 Neomycin Natural products 0.000 description 2
- 108090001146 Nuclear Receptor Coactivator 1 Proteins 0.000 description 2
- 108090001145 Nuclear Receptor Coactivator 3 Proteins 0.000 description 2
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 2
- 102100037226 Nuclear receptor coactivator 2 Human genes 0.000 description 2
- 102100030569 Nuclear receptor corepressor 2 Human genes 0.000 description 2
- 101710153660 Nuclear receptor corepressor 2 Proteins 0.000 description 2
- 108010047956 Nucleosomes Proteins 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 101150014691 PPARA gene Proteins 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 2
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 2
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 2
- 108010037522 Promyelocytic Leukemia Protein Proteins 0.000 description 2
- 102100026375 Protein PML Human genes 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 230000003081 coactivator Effects 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000013613 expression plasmid Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 238000003306 harvesting Methods 0.000 description 2
- 231100000334 hepatotoxic Toxicity 0.000 description 2
- 230000003082 hepatotoxic effect Effects 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006882 induction of apoptosis Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229960004927 neomycin Drugs 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 210000001623 nucleosome Anatomy 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229950009215 phenylbutanoic acid Drugs 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 150000004492 retinoid derivatives Chemical class 0.000 description 2
- 239000012723 sample buffer Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical class C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 1
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 1
- 102100024321 Alkaline phosphatase, placental type Human genes 0.000 description 1
- 102100021631 B-cell lymphoma 6 protein Human genes 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- 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 1
- 241000792859 Enema Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- 108091060211 Expressed sequence tag Proteins 0.000 description 1
- 208000034951 Genetic Translocation Diseases 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 102100039869 Histone H2B type F-S Human genes 0.000 description 1
- 102100022846 Histone acetyltransferase KAT2B Human genes 0.000 description 1
- 101710083341 Histone acetyltransferase KAT2B Proteins 0.000 description 1
- 101000971234 Homo sapiens B-cell lymphoma 6 protein Proteins 0.000 description 1
- 101001035372 Homo sapiens Histone H2B type F-S Proteins 0.000 description 1
- 101000602930 Homo sapiens Nuclear receptor coactivator 2 Proteins 0.000 description 1
- 101000974356 Homo sapiens Nuclear receptor coactivator 3 Proteins 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000004966 Nuclear Receptor Coactivator 1 Human genes 0.000 description 1
- 102100037223 Nuclear receptor coactivator 1 Human genes 0.000 description 1
- 108090001144 Nuclear receptor coactivator 2 Proteins 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 239000012979 RPMI medium 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
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 102000004408 Transcription factor TFIIB Human genes 0.000 description 1
- 108090000941 Transcription factor TFIIB Proteins 0.000 description 1
- 101100476214 Xenopus laevis runx1 gene Proteins 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- 101710185494 Zinc finger protein Proteins 0.000 description 1
- 102100023597 Zinc finger protein 816 Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 101150066984 aml gene Proteins 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000012742 biochemical analysis Methods 0.000 description 1
- 230000007698 birth defect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 230000008711 chromosomal rearrangement Effects 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 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
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 101150066555 lacZ gene Proteins 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000007431 microscopic evaluation Methods 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 208000030364 neural tube closure defect Diseases 0.000 description 1
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- 238000000424 optical density measurement Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000002135 phase contrast microscopy Methods 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 108010031345 placental alkaline phosphatase Proteins 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940077150 progesterone and estrogen Drugs 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 238000012342 propidium iodide staining Methods 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 230000007363 regulatory process Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000037426 transcriptional repression Effects 0.000 description 1
- 108091006107 transcriptional repressors Proteins 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229930185603 trichostatin Natural products 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP00114088.8 | 2000-07-07 | ||
| EP00114088A EP1170008A1 (en) | 2000-07-07 | 2000-07-07 | Valproic acid and derivatives thereof as histone deacetylase inhibitors |
| PCT/EP2001/007704 WO2002007722A2 (en) | 2000-07-07 | 2001-07-05 | Valproic acid and derivatives thereof as histone deacetylase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2414967A1 CA2414967A1 (en) | 2002-01-31 |
| CA2414967C true CA2414967C (en) | 2009-08-25 |
Family
ID=8169134
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002414967A Expired - Fee Related CA2414967C (en) | 2000-07-07 | 2001-07-05 | Valproic acid and derivatives thereof as histone deacetylase inhibitors |
Country Status (10)
| Country | Link |
|---|---|
| US (2) | US7265154B2 (enExample) |
| EP (2) | EP1170008A1 (enExample) |
| JP (1) | JP2004504347A (enExample) |
| AT (1) | ATE295725T1 (enExample) |
| AU (2) | AU8392501A (enExample) |
| CA (1) | CA2414967C (enExample) |
| DE (1) | DE60110912T2 (enExample) |
| ES (1) | ES2239677T3 (enExample) |
| PT (1) | PT1301184E (enExample) |
| WO (1) | WO2002007722A2 (enExample) |
Families Citing this family (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1170008A1 (en) | 2000-07-07 | 2002-01-09 | Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus | Valproic acid and derivatives thereof as histone deacetylase inhibitors |
| GB0024362D0 (en) * | 2000-10-05 | 2000-11-22 | Glaxo Group Ltd | Medicaments |
| WO2003018767A2 (en) * | 2001-08-27 | 2003-03-06 | Advanced Cell Technology, Inc. | Trans-differentiation and re-differentiation of somatic cells and production of cells for cell therapies |
| EP1293205A1 (en) * | 2001-09-18 | 2003-03-19 | G2M Cancer Drugs AG | Valproic acid and derivatives thereof for the combination therapy of human cancers, for the treatment of tumour metastasis and minimal residual disease |
| US6706686B2 (en) | 2001-09-27 | 2004-03-16 | The Regents Of The University Of Colorado | Inhibition of histone deacetylase as a treatment for cardiac hypertrophy |
| WO2003032921A2 (en) | 2001-10-16 | 2003-04-24 | Sloan-Kettering Institute For Cancer Research | Treatment of neurodegenerative diseases and cancer of the brain |
| AU2003220119A1 (en) | 2002-03-07 | 2003-09-22 | University Of Delaware | Methods, compositions, and kits for enhancing oligonucleotide-mediated nucleic acid sequence alteration using compositions comprising a histone deacetylase inhibitor, lambda phage beta protein, or hydroxyurea |
| IL149404A0 (en) * | 2002-04-29 | 2002-11-10 | Yissum Res Dev Co | METHODS AND COMPOSITIONS FOR MODULATING β-CATENIN PHOSPHORYLATION |
| US7154002B1 (en) | 2002-10-08 | 2006-12-26 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
| US7250514B1 (en) | 2002-10-21 | 2007-07-31 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
| GB0226855D0 (en) | 2002-11-18 | 2002-12-24 | Queen Mary & Westfield College | Histone deacetylase inhibitors |
| US20060247192A1 (en) * | 2002-12-05 | 2006-11-02 | Jenkinson John D | Control of apoptosis |
| US7244751B2 (en) | 2003-02-14 | 2007-07-17 | Shenzhen Chipscreen Biosciences Ltd. | Histone deacetylase inhibitors of novel benzamide derivatives with potent differentiation and anti-proliferation activity |
| KR20050122210A (ko) * | 2003-03-17 | 2005-12-28 | 다케다 샌디에고, 인코포레이티드 | 히스톤 탈아세틸화 효소 억제제 |
| EP1491188A1 (en) * | 2003-06-25 | 2004-12-29 | G2M Cancer Drugs AG | Topical use of valproic acid for the prevention or treatment of skin disorders |
| WO2005065681A1 (en) * | 2003-12-19 | 2005-07-21 | Takeda San Diego, Inc. | N- hydroxy-3-(3-(1h-imidazol-2-yl)-phenyl)-acrylamide derivatives and related compounds as histone deacetylase (hdac) inhibitors for the treatment of cancer |
| WO2005066151A2 (en) * | 2003-12-19 | 2005-07-21 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
| DE602004014723D1 (de) * | 2004-04-30 | 2008-08-14 | Desitin Arzneimittel Gmbh | Histondeacetylase-Inhibitor enthaltende Formulierung zur zweiphasigen Freisetzung |
| KR100659779B1 (ko) | 2004-09-04 | 2006-12-19 | 주식회사 바이넥스 | 히스톤 디아세틸라제 억제제를 함유하는 중간엽줄기세포의 골분화유도용 조성물 및 이를 이용한 골분화증가방법 |
| JP2008524246A (ja) * | 2004-12-16 | 2008-07-10 | タケダ サン ディエゴ インコーポレイテッド | ヒストンデアセチラーゼ阻害剤 |
| WO2006122319A2 (en) * | 2005-05-11 | 2006-11-16 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
| ZA200800901B (en) | 2005-07-14 | 2010-05-26 | Takeda San Diego Inc | Histone deacetylase inhibitors |
| WO2007084390A2 (en) * | 2006-01-13 | 2007-07-26 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
| WO2008011603A2 (en) * | 2006-07-20 | 2008-01-24 | Wisconsin Alumni Research Foundation | Modulating notch1 signaling pathway for treating neuroendocrine tumors |
| CA2661024A1 (en) * | 2006-08-28 | 2008-03-06 | The Regents Of The University Of California | Small molecule potentiator of hormonal therapy for breast cancer |
| GB0620823D0 (en) | 2006-10-19 | 2006-11-29 | Univ London | Histone deacetylase inhibitors |
| EP2091525A1 (en) * | 2006-12-06 | 2009-08-26 | Sapporo Medical University | Potentiation of cellular immunity using histone deacetylase (hdac) inhibitors |
| US20090023186A1 (en) * | 2007-07-22 | 2009-01-22 | Excellgene Sa | Use of valproic acid for enhancing production of recombinant proteins in mammalian cells |
| US8293513B2 (en) * | 2007-12-14 | 2012-10-23 | Georgetown University | Histone deacetylase inhibitors |
| US8623853B2 (en) | 2008-07-23 | 2014-01-07 | The Brigham And Women's Hospital, Inc. | Treatment of cancers characterized by chromosomal rearrangement of the NUT gene |
| ES2473792T3 (es) | 2009-04-03 | 2014-07-07 | Naturewise Biotech & Medicals Corporation | Compuestos cin�micos y derivados de los mismos para la inhibición de la histona desacetilasa |
| US7994357B2 (en) | 2009-04-03 | 2011-08-09 | Naturewise Biotech & Medicals Corporation | Cinamic compounds and derivatives therefrom for the inhibition of histone deacetylase |
| EP2277387B1 (en) | 2009-07-22 | 2016-10-19 | NatureWise Biotech & Medicals Corporation | New use of histone deacetylase inhibitors in changing mrjp3 protein in royal jelly |
| CN102575236B (zh) * | 2009-09-07 | 2014-10-01 | 贾瓦哈拉尔尼赫鲁高级科学研究中心 | 利用ctk7a抑制组蛋白乙酰转移酶及其方法 |
| US8921533B2 (en) | 2011-07-25 | 2014-12-30 | Chromatin Technologies | Glycosylated valproic acid analogs and uses thereof |
| US10184933B2 (en) | 2013-10-01 | 2019-01-22 | The J. David Gladstone Industries | Compositions, systems and methods for gene expression noise drug screening and uses thereof |
| KR20160145833A (ko) * | 2014-05-02 | 2016-12-20 | 온코에틱스 게엠베하 | 티에노트리아졸로디아제핀 화합물을 사용한 급성 골수성 백혈병 및/또는 급성 림프아구성 백혈병의 치료 방법 |
| CN105622712B (zh) * | 2014-10-27 | 2019-08-27 | 天津金耀集团有限公司 | 一种甾体3-酮-4-烯物合成工艺 |
| TWI808055B (zh) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Hdac 抑制劑與 pd-1 抑制劑之組合治療 |
| TWI794171B (zh) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Ｈｄａｃ抑制劑與ｐｄ-ｌ１抑制劑之組合治療 |
| US20210386787A1 (en) * | 2018-10-12 | 2021-12-16 | Life Technologies Corporation | Hematopoietic Stem and Progenitor Cell Expansion System |
| CN111358777A (zh) * | 2020-02-24 | 2020-07-03 | 军事科学院军事医学研究院环境医学与作业医学研究所 | 一种提高外周血单个核细胞线粒体功能的方法和应用 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6300373B1 (en) * | 1993-09-10 | 2001-10-09 | American Biogenetic Sciences, Inc. | Antiproliferative and neurotrophic molecules |
| US5672746A (en) * | 1994-08-30 | 1997-09-30 | American Biogenetic Sciences, Inc. | Antiproliferative and neurotrophic molecules |
| RO115498B1 (ro) * | 1993-10-29 | 2000-03-30 | Univ Boston | Metoda de tratament a neoplasmului |
| JPH11514857A (ja) * | 1995-09-20 | 1999-12-21 | メルク エンド カンパニー インコーポレーテッド | 抗原虫剤の標的としてのヒストンデアセチラーゼ |
| US6777217B1 (en) * | 1996-03-26 | 2004-08-17 | President And Fellows Of Harvard College | Histone deacetylases, and uses related thereto |
| WO1997047307A1 (en) * | 1996-06-14 | 1997-12-18 | The Uab Research Foundation | Use of histone deacetylase inhibitors to activate transgene expression |
| AU5617398A (en) * | 1996-12-30 | 1998-07-31 | Beacon Laboratories L.L.C. | Tricarboxylic acid-containing oxyalkyl esters and uses thereof |
| US6387673B1 (en) * | 1997-05-01 | 2002-05-14 | The Salk Institute For Biological Studies | Compounds useful for the modulation of processes mediated by nuclear hormone receptors, methods for the identification and use of such compounds |
| EP1037533A1 (en) * | 1997-11-10 | 2000-09-27 | The Salk Institute for Biological Studies | Methods for the use of inhibitors of co-repressors for the treatment of neoplastic diseases |
| US6262116B1 (en) * | 1998-01-23 | 2001-07-17 | Sloan-Kettering Institute For Cancer Research | Transcription therapy for cancers |
| EP1170008A1 (en) | 2000-07-07 | 2002-01-09 | Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus | Valproic acid and derivatives thereof as histone deacetylase inhibitors |
-
2000
- 2000-07-07 EP EP00114088A patent/EP1170008A1/en not_active Withdrawn
-
2001
- 2001-07-05 AU AU8392501A patent/AU8392501A/xx active Pending
- 2001-07-05 US US10/332,353 patent/US7265154B2/en not_active Expired - Fee Related
- 2001-07-05 DE DE60110912T patent/DE60110912T2/de not_active Expired - Lifetime
- 2001-07-05 WO PCT/EP2001/007704 patent/WO2002007722A2/en not_active Ceased
- 2001-07-05 CA CA002414967A patent/CA2414967C/en not_active Expired - Fee Related
- 2001-07-05 AU AU2001283925A patent/AU2001283925B2/en not_active Ceased
- 2001-07-05 PT PT01962831T patent/PT1301184E/pt unknown
- 2001-07-05 AT AT01962831T patent/ATE295725T1/de active
- 2001-07-05 ES ES01962831T patent/ES2239677T3/es not_active Expired - Lifetime
- 2001-07-05 JP JP2002513458A patent/JP2004504347A/ja not_active Ceased
- 2001-07-05 EP EP01962831A patent/EP1301184B1/en not_active Expired - Lifetime
-
2007
- 2007-01-17 US US11/653,855 patent/US20070232696A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20040087652A1 (en) | 2004-05-06 |
| US7265154B2 (en) | 2007-09-04 |
| WO2002007722A2 (en) | 2002-01-31 |
| EP1301184B1 (en) | 2005-05-18 |
| CA2414967A1 (en) | 2002-01-31 |
| DE60110912D1 (de) | 2005-06-23 |
| DE60110912T2 (de) | 2005-10-20 |
| ES2239677T3 (es) | 2005-10-01 |
| JP2004504347A (ja) | 2004-02-12 |
| US20070232696A1 (en) | 2007-10-04 |
| AU2001283925B2 (en) | 2005-07-14 |
| PT1301184E (pt) | 2005-07-29 |
| EP1170008A1 (en) | 2002-01-09 |
| WO2002007722A3 (en) | 2002-07-18 |
| AU8392501A (en) | 2002-02-05 |
| ATE295725T1 (de) | 2005-06-15 |
| EP1301184A2 (en) | 2003-04-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2001283925B2 (en) | Valproic acid and derivatives thereof as histone deacetylase inhibitors | |
| AU2001283925A1 (en) | Valproic acid and derivatives thereof as histone deacetylase inhibitors | |
| Nelson et al. | 13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes | |
| Rousseaux et al. | Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator–activated receptor-γ | |
| Clay et al. | Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells | |
| Fitzgerald et al. | Retinoic acid receptor α expression correlates with retinoid-induced growth inhibition of human breast cancer cells regardless of estrogen receptor status | |
| Ross et al. | Retinoids in embryonal development | |
| Nagpal et al. | Retinoid antagonism of NF-IL6: insight into the mechanism of antiproliferative effects of retinoids in Kaposi’s sarcoma | |
| Matsushima-Nishiwaki et al. | Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid | |
| Lea et al. | Inhibition of cell proliferation by potential peroxisome proliferator-activated receptor (PPAR) gamma agonists and antagonists | |
| Chintharlapalli et al. | 2-Cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor γ-dependent and-independent pathways | |
| Liu et al. | Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPARα/γ ligand TZD18 | |
| Polvani et al. | Nuclear receptors and pathogenesis of pancreatic cancer | |
| Yousefi et al. | Peroxisome proliferator‐activated receptor ligands and their role in chronic myeloid leukemia: Therapeutic strategies | |
| Hall-Glenn et al. | CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress | |
| JP2014076953A (ja) | レチノイドｘ受容体パーシャルアゴニスト化合物及びこのレチノイドｘ受容体パーシャルアゴニスト化合物を有効成分として含有する薬剤 | |
| Hallenborg et al. | Epidermis-type lipoxygenase 3 regulates adipocyte differentiation and peroxisome proliferator-activated receptor γ activity | |
| Suzui et al. | Acyclic retinoid activates retinoic acid receptor β and induces transcriptional activation of p21CIP1 in HepG2 human hepatoma cells | |
| Vourtsis et al. | Effect of an all-trans-retinoic acid conjugate with spermine on viability of human prostate cancer and endothelial cells in vitro and angiogenesis in vivo | |
| Wright et al. | Functional activation of PPARγ in human upper aerodigestive cancer cell lines | |
| Lee et al. | Interferon regulatory factor-1 (IRF-1) regulates VEGF-induced angiogenesis in HUVECs | |
| Hayashi et al. | Effect of 9-cis-retinoic acid on oral squamous cell carcinoma cell lines | |
| JP5885140B2 (ja) | Ｒｘｒパーシャルアゴニスト | |
| JP2007525492A (ja) | Ｐｒａｍｅ阻害剤とｈｄａｃ阻害剤との併用 | |
| Zhu et al. | PML-RARα stabilized by zinc in human acute promyelocytic leukemia NB4 cells |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |