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

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 than 118
diverse kinases showed no off-target kinase inhibition. Notably, by
addressing a selectivity pocket, PITCOIN4 showed nanomolar
inhibition of PI3K-C2α and >100-fold selectivity in a general
kinase panel. Our study paves the way for the development of novel
therapies for diseases related to PI3K-C2α function.