Updated project metadata. Phosphatidylinositol 3-kinase type 2a (PI3KC2a) and related class II PI 3-kinase isoforms are of rising biomedical interest because of their crucial roles in endocytic membrane dynamics, cell division and signalling, angiogenesis, and platelet morphology and function. Herein we report the development and characterization of PITCOINs, potent and highly selective small molecule inhibitors of PI3KC2 catalytic activity. PITCOIN compounds exhibit strong selectivity towards PI3KC2 due to their unique mode of interaction with the ATP binding site of the enzyme. We demonstrate that acute inhibition of PI3KC2-mediated synthesis of phosphatidylinositol 3-phosphates by PITCOINs impairs endocytic membrane dynamics and membrane remodelling during platelet-dependent thrombus formation. To our knowledge PITCOINs are the first potent and selective cell permeable inhibitors of PI3KC2a function with potential biomedical applications ranging from thrombosis to diabetes and cancer.