• Paolo Pevarello, 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, and Martha A Warpehoski.
• Chemistry Department, Pharmacia Italia, Viale Pasteur 10, 20014 Nerviano (MI), Italy. paolo.pevarello@pharmacia.com
• J. Med. Chem. 2004 Jun 17; 47 (13): 3367-80.

AbstractAbnormal 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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