3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding

  • J Med Chem. 2004 Jun 17;47(13):3367-80. doi: 10.1021/jm031145u.
Paolo Pevarello  1 ,  Maria Gabriella Brasca ,  Raffaella Amici ,  Paolo Orsini ,  Gabriella Traquandi ,  Luca Corti ,  Claudia Piutti ,  Pietro Sansonna ,  Manuela Villa ,  Betsy S Pierce ,  Maurizio Pulici ,  Patrizia Giordano ,  Katia Martina ,  Edward L Fritzen ,  Richard A Nugent ,  Elena Casale ,  Alexander Cameron ,  Marina Ciomei ,  Fulvia Roletto ,  Antonella Isacchi ,  GianPaolo Fogliatto ,  Enrico Pesenti ,  Wilma Pastori ,  Aurelio Marsiglio ,  Karen L Leach ,  Paula M Clare ,  Francesco Fiorentini ,  Mario Varasi ,  Anna Vulpetti ,  Martha A Warpehoski
Affiliations
  • 1. Chemistry Department, Pharmacia Italia, Viale Pasteur 10, 20014 Nerviano (MI), Italy. [email protected]
PMID: 15189033 DOI: 10.1021/jm031145u
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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