3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.
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.
Pevarello
Paolo
P
Chemistry Department, Pharmacia Italia, Viale Pasteur 10, 20014 Nerviano (MI), Italy. paolo.pevarello@pharmacia.com
Brasca
Maria Gabriella
MG
Amici
Raffaella
R
Orsini
Paolo
P
Traquandi
Gabriella
G
Corti
Luca
L
Piutti
Claudia
C
Sansonna
Pietro
P
Villa
Manuela
M
Pierce
Betsy S
BS
Pulici
Maurizio
M
Giordano
Patrizia
P
Martina
Katia
K
Fritzen
Edward L
EL
Nugent
Richard A
RA
Casale
Elena
E
Cameron
Alexander
A
Ciomei
Marina
M
Roletto
Fulvia
F
Isacchi
Antonella
A
Fogliatto
GianPaolo
G
Pesenti
Enrico
E
Pastori
Wilma
W
Marsiglio
Aurelio
A
Leach
Karen L
KL
Clare
Paula M
PM
Fiorentini
Francesco
F
Varasi
Mario
M
Vulpetti
Anna
A
Warpehoski
Martha A
MA
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
D000081:Acetamides; D000970:Antineoplastic Agents; D019925:Cyclin A; D011720:Pyrazoles; C487578:N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2