Development of selective inhibitors of phosphatidylinositol 3-kinase C2α

Phosphatidylinositol 3-kinase type 2 alpha (PI3KC2 alpha) and related class II PI3K isoforms are of increasing biomedical interest because of their crucial roles in endocytic membrane dynamics, cell division and signaling, angiogenesis, and platelet morphology and function. Herein we report the development and characterization of Phosphatidyllnositol Three-kinase Class twO INhibitors (PITCOINs), potent and highly selective small-molecule inhibitors of PI3KC2 alpha catalytic activity. PITCOIN compounds exhibit strong selectivity toward PI3KC2 alpha due to their unique mode of interaction with the ATP-binding site of the enzyme. We demonstrate that acute inhibition of PI3KC2 alpha-mediated synthesis of phosphatidylinositol 3-phosphates by PITCOINs impairs endocytic membrane dynamics and membrane remodeling during platelet-dependent thrombus formation. PITCOINs are potent and selective cell-permeable inhibitors of PI3KC2 alpha function with potential biomedical applications ranging from thrombosis to diabetes and cancer.

Automated summary

In this study, we developed a novel PI3KC2 alpha catalytic activity inhibitor PITCOIN, which exhibits strong selectivity towards PI3KC2 alpha due to its unique mode of interaction with the ATP-binding site of the enzyme. It was demonstrated that PITCOINs can inhibit the PI3KC2 alpha-mediated synthesis of phosphatidylinositol 3-phosphates, impairing endocytic membrane dynamics and platelet-dependent thrombus formation.