Discovery of a Potent, Selective, and Orally Bioavailable Pyridinyl-Pyrimidine Phthalazine Aurora Kinase Inhibitor
作者
CEE VICTOR J; SCHENKEL LAURIE B; HODOUS BRIAN L; DEAK HOLLY L; NGUYEN HANH N; OLIVIERI PHILIP R; ROMERO KARINA; BAK ANNETTE; BE XUHAI; BELLON STEVE; BUSH TAMMY L; CHENG ALAN C; CHUNG GRACE; COATS STEVE; EDEN PATRICK M; HANESTAD KELLY; GALLANT PAUL L; GU YAN; HUANG XIN; KENDALL RICHARD L; LIN MINHWA JASMINE; MORRISON MICHAEL J; PATEL VINOD F; RADINSKY ROBERT; ROSE PAUL E; ROSS SANDRA; SUN JIRONG; TANG JIN; ZHAO HUILIN; PAYTON MARC; GEUNSMEYER STEPHANIE D
[摘要]：The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 86 at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.
