3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.
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.
Mesh Terms:
Acetamides, Animals, Antineoplastic Agents, Binding Sites, CDC2-CDC28 Kinases, Cell Line, Tumor, Crystallography, X-Ray, Cyclin A, Cyclin-Dependent Kinase 2, Drug Screening Assays, Antitumor, Humans, Mice, Mice, Inbred BALB C, Models, Molecular, Neoplasm Transplantation, Pyrazoles, Structure-Activity Relationship, Transplantation, Heterologous
Acetamides, Animals, Antineoplastic Agents, Binding Sites, CDC2-CDC28 Kinases, Cell Line, Tumor, Crystallography, X-Ray, Cyclin A, Cyclin-Dependent Kinase 2, Drug Screening Assays, Antitumor, Humans, Mice, Mice, Inbred BALB C, Models, Molecular, Neoplasm Transplantation, Pyrazoles, Structure-Activity Relationship, Transplantation, Heterologous
J. Med. Chem.
Date: Jun. 17, 2004
PubMed ID: 15189033
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