Development of selective inhibitors of phosphatidylinositol 3-kinase C2α

Nat Chem Biol. 2022 Sep 15. doi: 10.1038/s41589-022-01118-z.

Wen-Ting Lo ^# ¹, Hassane Belabed ^# ¹, Murat Kücükdisli ^# ¹, Juliane Metag ¹, Yvette Roske ², Polina Prokofeva ³, Yohei Ohashi ⁴, André Horatscheck ¹, Davide Cirillo ¹, Michael Krauss ¹, Christopher Schmied ¹, Martin Neuenschwander ¹, Jens Peter von Kries ¹, Guillaume Médard ³, Bernhard Kuster ³, Olga Perisic ⁴, Roger L Williams ⁴, Oliver Daumke ², Bernard Payrastre ⁵ ⁶, Sonia Severin ⁵, Marc Nazaré ⁷, Volker Haucke ⁸ ⁹

Affiliations

1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
2 Max-Delbrück-Centrum für Molekulare Medizin, Kristallographie, Berlin, Germany.
3 Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.
4 MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.
5 Inserm, U1297-Université, Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France.
6 Centre Hospitalier Universitaire de Toulouse, Laboratoire d'Hématologie, Toulouse, France.
7 Departments of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, Berlin, Germany. [email protected].
8 Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany. [email protected].
9 Departments of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, Berlin, Germany. [email protected].
# Contributed equally.

PMID: 36109648 DOI: 10.1038/s41589-022-01118-z

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.

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