TY - JOUR
T1 - Development of selective inhibitors of phosphatidylinositol 3-kinase C2α
AU - Lo, Wen Ting
AU - Belabed, Hassane
AU - Kücükdisli, Murat
AU - Metag, Juliane
AU - Roske, Yvette
AU - Prokofeva, Polina
AU - Ohashi, Yohei
AU - Horatscheck, André
AU - Cirillo, Davide
AU - Krauss, Michael
AU - Schmied, Christopher
AU - Neuenschwander, Martin
AU - von Kries, Jens Peter
AU - Médard, Guillaume
AU - Kuster, Bernhard
AU - Perisic, Olga
AU - Williams, Roger L.
AU - Daumke, Oliver
AU - Payrastre, Bernard
AU - Severin, Sonia
AU - Nazaré, Marc
AU - Haucke, Volker
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2023/1
Y1 - 2023/1
N2 - 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. [Figure not available: see fulltext.].
AB - 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. [Figure not available: see fulltext.].
UR - http://www.scopus.com/inward/record.url?scp=85138290296&partnerID=8YFLogxK
U2 - 10.1038/s41589-022-01118-z
DO - 10.1038/s41589-022-01118-z
M3 - Article
C2 - 36109648
AN - SCOPUS:85138290296
SN - 1552-4450
VL - 19
SP - 18
EP - 27
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 1
ER -