Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition.

ABSTRACT: Class II phosphoinositide-3-kinases (PI3Ks) play central roles in cell signaling, division, migration, and survival. Despite evidence that all PI3K class II isoforms serve unique cellular functions, the lack of isoform-selective inhibitors severely hampers the systematic investigation of their potential relevance as pharmacological targets. Here, we report the structural evaluation and molecular determinants for selective PI3K-C2α inhibition by a structure-activity relationship study based on a pteridinone scaffold, leading to the discovery of selective PI3K-C2α inhibitors called PITCOINs. Cocrystal structures and docking experiments supported the rationalization of the structural determinants essential for inhibitor activity and high selectivity. Profiling of PITCOINs in a panel of more t

SUBMITTER: Kucukdisli M 

PROVIDER: S-EPMC11151210 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature