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

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

Affiliation

  • 1 Chemistry Department, Pharmacia Italia, Viale Pasteur 10, 20014 Nerviano (MI), Italy. paolo.pevarello@pharmacia.com
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-123045
    CDK2 Inhibitor
    CDK