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

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

Cite this

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title = "Discovery and antiplatelet activity of a selective PI3Kβ inhibitor (MIPS-9922)",
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.",
keywords = "Kinase selectivity, PI3 kinase, Platelet aggregation inhibitors, Thrombosis",
author = "Zhaohua Zheng and Pinson, {Jo Anne} and Mountford, {Simon J.} and Stephanie Orive and Schoenwaelder, {Simone M.} and David Shackleford and Andrew Powell and Nelson, {Erin M.} and Hamilton, {Justin R.} and Shaun Jackson and Jennings, {Ian G.} and Thompson, {Philip E.}",
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language = "English",
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Discovery and antiplatelet activity of a selective PI3Kβ inhibitor (MIPS-9922). / Zheng, Zhaohua; Pinson, Jo Anne; Mountford, Simon J.; Orive, Stephanie; Schoenwaelder, Simone M.; Shackleford, David; Powell, Andrew; Nelson, Erin M.; Hamilton, Justin R.; Jackson, Shaun; Jennings, Ian G.; Thompson, Philip E.

In: European Journal of Medicinal Chemistry, Vol. 122, 21.10.2016, p. 339-351.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Zheng, Zhaohua

AU - Pinson, Jo Anne

AU - Mountford, Simon J.

AU - Orive, Stephanie

AU - Schoenwaelder, Simone M.

AU - Shackleford, David

AU - Powell, Andrew

AU - Nelson, Erin M.

AU - Hamilton, Justin R.

AU - Jackson, Shaun

AU - Jennings, Ian G.

AU - Thompson, Philip E.

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AB - 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.

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