1vyz

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spinqualitylabelsall models PDB ID 1vyz Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
, resolution 2.21Å
Sites:
Ligands:
Activity:	Transferred entry: 2.7.11.1, with EC number 2.7.1.37
Coordinates:	save as pdb, mmCIF, xml

STRUCTURE OF CDK2 COMPLEXED WITH PNU-181227

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

1VYZ is a Single protein structure of sequence from Homo sapiens. 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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