Discovery and antiplatelet activity of a selective PI3Kβ inhibitor (MIPS-9922)

Zhaohua Zheng, Jo Anne Pinson, Simon J. Mountford, Stephanie Orive, Simone M. Schoenwaelder, David Shackleford, Andrew Powell, Erin M. Nelson, Justin R. Hamilton, Shaun Jackson, Ian G. Jennings, Philip E. Thompson

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)

Abstract

A series of amino-substituted triazines were developed and examined for PI3Kβ inhibition and anti-platelet function. Structural adaptations of a morpholine ring of the prototype pan-PI3K inhibitor ZSTK474 yielded PI3Kβ selective compounds, where the selectivity largely derives from an interaction with the non-conserved Asp862 residue, as shown by site directed mutagenesis. The most PI3Kβ selective inhibitor from the series was studied in detail through a series of in vitro and in vivo functional studies. MIPS-9922, 10 potently inhibited ADP-induced washed platelet aggregation. It also inhibited integrin αIIbβ3 activation and αIIbβ3 dependent platelet adhesion to immobilized vWF under high shear. It prevented arterial thrombus formation in the in vivo electrolytic mouse model of thrombosis without inducing prolonged bleeding or excess blood loss.

Original languageEnglish
Pages (from-to)339-351
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume122
DOIs
Publication statusPublished - 21 Oct 2016

Keywords

  • Kinase selectivity
  • PI3 kinase
  • Platelet aggregation inhibitors
  • Thrombosis

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