TY - JOUR
T1 - 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding
AU - Pevarello, Paolo
AU - Brasca, Maria Gabriella
AU - Amici, Raffaella
AU - Orsini, Paolo
AU - Traquandi, Gabriella
AU - Corti, Luca
AU - Piutti, Claudia
AU - Sansonna, Pietro
AU - Villa, Manuela
AU - Pierce, Betsy S.
AU - Pulici, Maurizio
AU - Giordano, Patrizia
AU - Martina, Katia
AU - Fritzen, Edward L.
AU - Nugent, Richard A.
AU - Casale, Elena
AU - Cameron, Alexander
AU - Ciomei, Marina
AU - Roletto, Fulvia
AU - Isacchi, Antonella
AU - Fogliatto, GianPaolo
AU - Pesenti, Enrico
AU - Pastori, Wilma
AU - Marsiglio, Aurelio
AU - Leach, Karen L.
AU - Clare, Paula M.
AU - Fiorentini, Francesco
AU - Varasi, Mario
AU - Vulpetti, Anna
AU - Warpehoski, Martha A.
PY - 2004/6/17
Y1 - 2004/6/17
N2 - 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.
AB - 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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U2 - 10.1021/jm031145u
DO - 10.1021/jm031145u
M3 - Article
C2 - 15189033
AN - SCOPUS:2942522534
VL - 47
SP - 3367
EP - 3380
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 13
ER -