3-Aminopyrazole Inhibitors of CDK2/Cyclin A as Antitumor Agents. 1. Lead Finding

• Published in: Journal of medicinal chemistry Vol. 47; no. 13; pp. 3367 - 3380
• Main Authors: Pevarello, Paolo, Brasca, Maria Gabriella, Amici, Raffaella, Orsini, Paolo, Traquandi, Gabriella, Corti, Luca, Piutti, Claudia, Sansonna, Pietro, Villa, Manuela, Pierce, Betsy S, Pulici, Maurizio, Giordano, Patrizia, Martina, Katia, Fritzen, Edward L, Nugent, Richard A, Casale, Elena, Cameron, Alexander, Ciomei, Marina, Roletto, Fulvia, Isacchi, Antonella, Fogliatto, GianPaolo, Pesenti, Enrico, Pastori, Wilma, Marsiglio, Aurelio, Leach, Karen L, Clare, Paula M, Fiorentini, Francesco, Varasi, Mario, Vulpetti, Anna, Warpehoski, Martha A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17-06-2004
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites; CDC2-CDC28 Kinases - antagonists & inhibitors; CDC2-CDC28 Kinases - chemistry; Cell Line, Tumor; Crystallography, X-Ray; Cyclin A - antagonists & inhibitors; Cyclin A - chemistry; Cyclin-Dependent Kinase 2; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Inbred BALB C; Models, Molecular; Neoplasm Transplantation; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Structure-Activity Relationship; Transplantation, Heterologous
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm031145u

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.