학술논문
Development of selective inhibitors of phosphatidylinositol 3-kinase C2α
Document Type
Article
Author
Lo, Wen-Ting; Belabed, Hassane; Kücükdisli, Murat; Metag, Juliane; Roske, Yvette; Prokofeva, Polina; Ohashi, Yohei; Horatscheck, André; Cirillo, Davide; Krauss, Michael; Schmied, Christopher; Neuenschwander, Martin; von Kries, Jens Peter; Médard, Guillaume; Kuster, Bernhard; Perisic, Olga; Williams, Roger L.; Daumke, Oliver; Payrastre, Bernard; Severin, Sonia; Nazaré, Marc; Haucke, Volker
Source
Nature Chemical Biology; 20220101, Issue: Preprints p1-10, 10p
Subject
Language
ISSN
15524450; 15524469
Abstract
Phosphatidylinositol 3-kinase type 2α (PI3KC2α) 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 PhosphatidylInositol Three-kinase Class twO INhibitors (PITCOINs), potent and highly selective small-molecule inhibitors of PI3KC2α catalytic activity. PITCOIN compounds exhibit strong selectivity toward PI3KC2α due to their unique mode of interaction with the ATP-binding site of the enzyme. We demonstrate that acute inhibition of PI3KC2α-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 PI3KC2α function with potential biomedical applications ranging from thrombosis to diabetes and cancer.