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Development of selective inhibitors of phosphatidylinositol 3-kinase C2α

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Item Type:Article
Title:Development of selective inhibitors of phosphatidylinositol 3-kinase C2α
Creators Name:Lo, W.T. and Belabed, H. and Kücükdisli, M. and Metag, J. and Roske, Y. and Prokofeva, P. and Ohashi, Y. and Horatscheck, A. and Cirillo, D. and Krauss, M. and Schmied, C. and Neuenschwander, M. and von Kries, J.P. and Médard, G. and Kuster, Be. and Perisic, O. and Williams, R.L. and Daumke, O. and Payrastre, B. and Severin, S. and Nazaré, M. and Haucke, V.
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.
Keywords:Membrane Trafficking, Small Molecules, X-Ray Crystallography, Animals, Mice
Source:Nature Chemical Biology
ISSN:1552-4450
Publisher:Nature Publishing Group
Date:15 September 2022
Official Publication:https://doi.org/10.1038/s41589-022-01118-z
PubMed:View item in PubMed

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