3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.
J Med Chem
; 47(13): 3367-80, 2004 Jun 17.
Article
em En
| MEDLINE
| ID: mdl-15189033
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Ciclina A
/
Quinases relacionadas a CDC2 e CDC28
/
Acetamidas
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article