A Structure-Based Approach to Selective PI3Kbeta Inihibition

Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles.Single PI3K isoforms differentially control tumorigenesis and PI3Kb has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors.Herein we describe the discovery and optimization of a new series of benzimidazole-and benzoxazole-pyrimidones as small molecular mass PI3Kb-selective inhibitors [1].Starting with compound 5 obtained from a one pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kb, and adequate in vitro pharmacokinetic properties.The X-Ray co-structure of compound 8 in PI3Kd showed key interactions and structural features supporting the observed PI3Kb isoform selectivity.Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.