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4-Arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects
dc.creator | Kryštof, V. | en |
dc.creator | Cankař, P. | en |
dc.creator | Fryšová, I. | en |
dc.creator | Slouka, J. | en |
dc.creator | Kontopidis, G. | en |
dc.creator | Džubák, P. | en |
dc.creator | Hajdúch, M. | en |
dc.creator | Srovnal, J. | en |
dc.creator | De Azevedo Jr, W. F. | en |
dc.creator | Orság, M. | en |
dc.creator | Paprskářová, M. | en |
dc.creator | Rolčík, J. | en |
dc.creator | Látr, A. | en |
dc.creator | Fischer, P. M. | en |
dc.creator | Strnad, M. | en |
dc.date.accessioned | 2015-11-23T10:37:08Z | |
dc.date.available | 2015-11-23T10:37:08Z | |
dc.date.issued | 2006 | |
dc.identifier | 10.1021/jm0605740 | |
dc.identifier.issn | 222623 | |
dc.identifier.uri | http://hdl.handle.net/11615/30062 | |
dc.description.abstract | In a routine screening of our small-molecule compound collection we recently identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study based on 35 analogues suggests ways in which the pharmacophore could be further optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics studies with the lead compound and X-ray crystallography of an inhibitor-CDK2 complex demonstrated that its mode of inhibition is competitive. Functional kinase assays confirmed the selectivity toward CDKs, with a preference for CDK9-cyclin T1. The most potent inhibitor, 4-[(3,5-diamino-1H-pyrazol-4-yl) diazenyl]phenol 31b (CAN508), reduced the frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation assays. Further observed cellular effects included decreased phosphorylation of the retinoblastoma protein and the C-terminal domain of RNA polymerase II, inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53, all of which are consistent with inhibition of CDK9. © 2006 American Chemical Society. | en |
dc.source.uri | http://www.scopus.com/inward/record.url?eid=2-s2.0-33750434863&partnerID=40&md5=a3d7049aab376f0a5859fd1df5e2d672 | |
dc.subject | 4 [(3,5 diamino 1h pyrazol 4yl)diazenyl]phenol | en |
dc.subject | 4 azo 3,5 diamino 1h pyrazole derivative | en |
dc.subject | adenosine triphosphate | en |
dc.subject | can 508 | en |
dc.subject | cyclin dependent kinase 2 | en |
dc.subject | cyclin dependent kinase 9 | en |
dc.subject | cyclin dependent kinase inhibitor | en |
dc.subject | cyclin E | en |
dc.subject | cyclin T1 | en |
dc.subject | messenger RNA | en |
dc.subject | polycyclic aromatic hydrocarbon derivative | en |
dc.subject | protein p53 | en |
dc.subject | pyrazole derivative | en |
dc.subject | retinoblastoma protein | en |
dc.subject | RNA polymerase II | en |
dc.subject | roscovitine | en |
dc.subject | unclassified drug | en |
dc.subject | animal cell | en |
dc.subject | article | en |
dc.subject | cancer cell culture | en |
dc.subject | carboxy terminal sequence | en |
dc.subject | cell cycle | en |
dc.subject | cell cycle S phase | en |
dc.subject | cell proliferation | en |
dc.subject | cell strain ht 29 | en |
dc.subject | competitive inhibition | en |
dc.subject | controlled study | en |
dc.subject | crystal structure | en |
dc.subject | drug potency | en |
dc.subject | drug screening | en |
dc.subject | drug selectivity | en |
dc.subject | enzyme assay | en |
dc.subject | enzyme inhibition | en |
dc.subject | enzyme inhibitor complex | en |
dc.subject | enzyme kinetics | en |
dc.subject | human | en |
dc.subject | human cell | en |
dc.subject | messenger RNA synthesis | en |
dc.subject | nonhuman | en |
dc.subject | nucleotide sequence | en |
dc.subject | pharmacophore | en |
dc.subject | protein induction | en |
dc.subject | protein phosphorylation | en |
dc.subject | structure activity relation | en |
dc.subject | transcription regulation | en |
dc.subject | X ray crystallography | en |
dc.subject | Antimetabolites | en |
dc.subject | Azo Compounds | en |
dc.subject | Bromodeoxyuridine | en |
dc.subject | Cell Line, Tumor | en |
dc.subject | Crystallography, X-Ray | en |
dc.subject | Cyclin-Dependent Kinase 2 | en |
dc.subject | Cyclin-Dependent Kinases | en |
dc.subject | Enzyme Inhibitors | en |
dc.subject | Humans | en |
dc.subject | Immunoblotting | en |
dc.subject | Models, Molecular | en |
dc.subject | Pyrazoles | en |
dc.subject | Reverse Transcriptase Polymerase Chain Reaction | en |
dc.subject | Reverse Transcription | en |
dc.subject | RNA | en |
dc.subject | Structure-Activity Relationship | en |
dc.subject | Substrate Specificity | en |
dc.title | 4-Arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects | en |
dc.type | journalArticle | en |
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