1vyw

From Proteopedia

Revision as of 16:13, 18 December 2007

STRUCTURE OF CDK2/CYCLIN A WITH PNU-292137

Overview

Abnormal proliferation mediated by disruption of the normal cell cycle, mechanisms is a hallmark of virtually all cancer cells. Compounds, targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase, activity are regarded as promising antitumor agents to complement the, existing therapies. From a high-throughput screening effort, we identified, a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of, this class is described. X-ray crystallographic data of early compounds in, this series, as well as in vitro testing funneled for rapidly achieving in, vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A, (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a, mouse xenograft model at a dose devoid of toxic effects.

About this Structure

1VYW is a Protein complex structure of sequences from Homo sapiens with SO4 and 292 as ligands. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding., Pevarello P, Brasca MG, Amici R, Orsini P, Traquandi G, Corti L, Piutti C, Sansonna P, Villa M, Pierce BS, Pulici M, Giordano P, Martina K, Fritzen EL, Nugent RA, Casale E, Cameron A, Ciomei M, Roletto F, Isacchi A, Fogliatto G, Pesenti E, Pastori W, Marsiglio A, Leach KL, Clare PM, Fiorentini F, Varasi M, Vulpetti A, Warpehoski MA, J Med Chem. 2004 Jun 17;47(13):3367-80. PMID:15189033

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