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

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 IsacchiGianPaolo Fogliatto, Enrico Pesenti, Wilma Pastori, Aurelio Marsiglio, Karen L. Leach, Paula M. Clare, Francesco Fiorentini, Mario Varasi, Anna Vulpetti, Martha A. Warpehoski

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3367-3380
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number13
Publication statusPublished - Jun 17 2004

ASJC Scopus subject areas

  • Organic Chemistry

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