4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects

0098696 - ÚEB 2008 RIV US eng J - Článek v odborném periodiku
Kryštof, Vladimír - Cankař, Petr - Fryšová, I. - Slouka, J. - Kontopidis, G. - Džubák, P. - Hajdúch, M. - Srovnal, J. - de Azevedo Jr., W.F. - Orság, Martin - Paprskářová, Martina - Rolčík, Jakub - Látr, Aleš - Fischer, P.M. - Strnad, Miroslav
4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
[4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.]
Journal of Medicinal Chemistry. Roč. 49, č. 22 (2006), s. 6500-6509. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA ČR GA301/05/0418
Výzkumný záměr: CEZ:AV0Z50380511
Zdroj financování: V - jiné veřejné zdroje
Klíčová slova: DEPENDENT KINASE INHIBITORS * POLYMERASE-II TRANSCRIPTION * TUMOR-NECROSIS-FACTOR
Kód oboru RIV: CE - Biochemie
Impakt faktor: 5.115, rok: 2006

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 CDK9cyclin 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.

4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
Trvalý link: http://hdl.handle.net/11104/0157542