title: 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.
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.
authors.affiliation: Chemistry Department, Pharmacia Italia, Viale Pasteur 10, 20014 Nerviano (MI), Italy. paolo.pevarello@pharmacia.com
authors.forename: Paolo
authors.initials: P
authors.lastname: Pevarello
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Brasca
authors.forename: Raffaella
authors.initials: R
authors.lastname: Amici
authors.forename: Paolo
authors.initials: P
authors.lastname: Orsini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Traquandi
authors.forename: Luca
authors.initials: L
authors.lastname: Corti
authors.forename: Claudia
authors.initials: C
authors.lastname: Piutti
authors.forename: Pietro
authors.initials: P
authors.lastname: Sansonna
authors.forename: Manuela
authors.initials: M
authors.lastname: Villa
authors.forename: Betsy S
authors.initials: BS
authors.lastname: Pierce
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pulici
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giordano
authors.forename: Katia
authors.initials: K
authors.lastname: Martina
authors.forename: Edward L
authors.initials: EL
authors.lastname: Fritzen
authors.forename: Richard A
authors.initials: RA
authors.lastname: Nugent
authors.forename: Elena
authors.initials: E
authors.lastname: Casale
authors.forename: Alexander
authors.initials: A
authors.lastname: Cameron
authors.forename: Marina
authors.initials: M
authors.lastname: Ciomei
authors.forename: Fulvia
authors.initials: F
authors.lastname: Roletto
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.forename: GianPaolo
authors.initials: G
authors.lastname: Fogliatto
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Wilma
authors.initials: W
authors.lastname: Pastori
authors.forename: Aurelio
authors.initials: A
authors.lastname: Marsiglio
authors.forename: Karen L
authors.initials: KL
authors.lastname: Leach
authors.forename: Paula M
authors.initials: PM
authors.lastname: Clare
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.forename: Anna
authors.initials: A
authors.lastname: Vulpetti
authors.forename: Martha A
authors.initials: MA
authors.lastname: Warpehoski
mesh_terms: 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
chemical_list: 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