4-Arylazo-3,5-diamino-1H-pyrazole CDK Inhibitors: SAR Study, Crystal Structure in Complex with CDK2, Selectivity, and Cellular Effects.

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F06%3A00002647" target="_blank" >RIV/61989592:15310/06:00002647 - isvavai.cz</a>

Alternative codes found

RIV/61989592:15110/06:00003490 RIV/61389030:_____/06:00098696

Result on the web

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DOI - Digital Object Identifier

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Result language

angličtina

Original language name

4-Arylazo-3,5-diamino-1H-pyrazole CDK Inhibitors: SAR Study, Crystal Structure in Complex with CDK2, Selectivity, and Cellular Effects.

Original language description

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 ofthe 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 i

Czech name

4-Arylazo-3,5-diamino-1H-pyrazolové inhibitory CDK: SAR Studie, krystalová struktura komplexu s CDK2, selektivita a buněčné účinky

Czech description

Rutinním screeningem naší sbírky malých molekul jsme identifikovali diamino-1H-pyrazoly jako novou skupinu ATP antagonistů se mírným účinkem vůči CDK2-cyklinu E. Pilotní analýza struktury a účinku založená na studiu 35 různých analogů navrhla cesty kterými může být farmakofor dále optimalizován a to skrze substituce 4-aryl prstence. Enzymatické a kinetické studie s hlavními sloučeninami a RTG krystalografie komplexu inhibitor-CDK2 demonstrovaly, že mechanismus inhibice je kompetitivní. Funkční kinázovéeseje potvrdily selektivitu vůči CDK s preferencí vůči CDK9-cyklinuT1.

Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

CE - Biochemistry

OECD FORD branch

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Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

Z - Vyzkumny zamer (s odkazem do CEZ)

Publication year

2006

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

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Volume of the periodical

49

Issue of the periodical within the volume

22

Country of publishing house

US - UNITED STATES

Number of pages

10

Pages from-to

6500-6509

UT code for WoS article

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EID of the result in the Scopus database

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