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

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

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rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
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 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 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 (en)
Title	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. (en)
skos:prefLabel	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. (en)
skos:notation	RIV/61989592:15310/06:00002647!RIV10-MSM-15310___
http://linked.open...avai/riv/aktivita	P V Z
http://linked.open...avai/riv/aktivity	P(GA301/05/0418), P(GP204/03/D231), V, Z(AV0Z50380511), Z(MSM6198959216)
http://linked.open...iv/cisloPeriodika	22
http://linked.open...vai/riv/dodaniDat	2010
http://linked.open...aciTvurceVysledku	Kryštof, Vladimír Rolčík, Jakub Strnad, Miroslav SROVNAL, Josef Fryšová, Iveta Džubák, Petr Hajdúch, Marián Cankař, Petr Slouka, Jan
http://linked.open.../riv/druhVysledku	J - Článek v odborném periodiku
http://linked.open...iv/duvernostUdaju	S - Úplné a pravdivé údaje nepodléhající ochraně podle zvláštních právních předpisů
http://linked.open...titaPredkladatele	Univerzita Palackého v Olomouci / Přírodovědecká fakulta
http://linked.open...dnocenehoVysledku	510682
http://linked.open...ai/riv/idVysledku	RIV/61989592:15310/06:00002647
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	4-arylazo-3,5-diamino-1H-pyrazoles; inhibitor-CDK2; RNA polymerase II; inhibition of CDK9. (en)
http://linked.open.../riv/klicoveSlovo	RNA polymerase II 4-arylazo-3 5-diamino-1H-pyrazoles inhibition of CDK9. inhibitor-CDK2
http://linked.open...odStatuVydavatele	US - Spojené státy americké
http://linked.open...ontrolniKodProRIV	[98235C7EC78B]
http://linked.open...i/riv/nazevZdroje	Journal of Medicinal Chemistry
http://linked.open...in/vavai/riv/obor	CE
http://linked.open...ichTvurcuVysledku	9 (xsd:int)
http://linked.open...cetTvurcuVysledku	15 (xsd:int)
http://linked.open...vavai/riv/projekt	New generations of cyclin-dependent kinase inhibitors with significant anticancer properties Biological activity of new inhibitors of cyclin-dependent kinases
http://linked.open...UplatneniVysledku	2006
http://linked.open...v/svazekPeriodika	49
http://linked.open...iv/tvurceVysledku	Džubák, Petr Hajdúch, Marián Kryštof, Vladimír Rolčík, Jakub Strnad, Miroslav Cankař, Petr Látr, Aleš Srovnal, Josef Fryšová, Iveta Slouka, Jan Paprskářová, Martina Fischer, Peter M. Orság, Martin Kontopidis, George de Azevedo Jr., Walter F.
http://linked.open...n/vavai/riv/zamer	Mechanismy regulace růstu a vývoje rostlin na úrovni buněk, orgánů a celých organismů: fyziologické, genetické a molekulárně biologické základy Modulation of signalling and regulatory pathways in normal and cancer cells
issn	0022-2623
number of pages	10 (xsd:int)
http://localhost/t...ganizacniJednotka	15310

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