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First Generation PI3KC2α Inhibitors are Potently Anti-Thrombotic and Improve on the Safety Profile of Current Anti-Platelet Therapies
ISTH Academy. Moon M. Jul 10, 2019; 274013; OC 78.3
Mitchell Moon
Mitchell Moon
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OC 78.3

First Generation PI3KC2α Inhibitors are Potently Anti-Thrombotic and Improve on the Safety Profile of Current Anti-Platelet Therapies

M. Moon1, M. Selvadurai1, S. Mountford2, R. Brazilek1, J.-Y. Rinckel3, A. Eckly3, C. Gachet3, W. Nesbitt1,4, P. Thompson2, J. Hamilton1
1Monash University, Australian Centre for Blood Diseases, Melbourne, Australia, 2Monash University, Medicinal Chemistry, Melbourne, Australia, 3Université de strasbourg, Strasbourg, France, 4RMIT University, Microplatforms research group, Melbourne, Australia

Main Topic: Platelets and Megakaryocytes
Category: Platelet Antagonists & Novel Therapeutics

Background: The class II PI3K, PI3KC2α, is a lipid kinase expressed in many cells, including platelets. Mice genetically deficient in PI3KC2α are protected against thrombosis but do not bleed. The mechanism behind this effect is incompletely understood but is believed to involve a dilation of the platelet internal membrane, the open canalicular system (OCS). However, due to an absence of PI3KC2α inhibitors, whether or not a similar mechanism exists in human platelets remains unknown.
Aims: To determine the efficacy of first generation PI3KC2α inhibitors and to assess the viability of PI3KC2α as a target for novel anti-platelet therapies.
Methods: A rational drug design approach was used to develop PI3KC2α inhibitors which were tested for their effects on recombinant PI3KC2α, isolated platelets, ex vivo whole blood thrombosis, and mouse models of in vivo thrombosis.
Results: MIPS-19416 emerged as a lead inhibitor, with an IC50 of 13 nM against recombinant enzyme. MIPS-19416 completely reproduced the unique changes to the OCS in mouse platelets and induced near-identical effects in human platelets. MIPS-19416 only modestly impaired in vitro human platelet activation (aggregation, P-selectin expression, αIIbβ3 activation) but was potently anti-thrombotic in whole blood experiments. Mice treated with MIPS-19416 were protected against thrombosis in two distinct in vivo thrombosis models, but did not exhibit impaired haemostasis. Finally, MIPS-19416 markedly impaired human ex vivo thrombosis that was resistant to broad inhibition of platelet activation pathways (thrombin, ADP and thromboxane).
Conclusions: Development of a first generation PI3KC2α inhibitor revealed that PI3KC2α regulates the OCS in both mouse and human platelets. Inhibition of PI3KC2α produced an anti-thrombotic effect not fully explained by the modest effects on platelet activation and may be largely independent of canonical platelet activation. These findings reveal a novel target for the development of anti-thrombotic therapies with an improved safety profile over current approaches.

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