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 P Jackson; Ian G Jennings; Philip E Thompson

doi:10.1016/j.ejmech.2016.06.010

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

Eur J Med Chem. 2016 Oct 21:122:339-351. doi: 10.1016/j.ejmech.2016.06.010. Epub 2016 Jun 10.

Affiliations

¹ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Prahran, Victoria 3004, Australia.
² Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
³ Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Prahran, Victoria 3004, Australia.
⁴ Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
⁵ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: philip.thompson@monash.edu.

PMID: 27387421
DOI: 10.1016/j.ejmech.2016.06.010

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.

MeSH terms

Animals
Drug Discovery*
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Humans
Male
Mice
Phosphoinositide-3 Kinase Inhibitors*
Platelet Aggregation / drug effects
Platelet Aggregation Inhibitors / pharmacokinetics
Platelet Aggregation Inhibitors / pharmacology*
Rats
Triazines / pharmacokinetics
Triazines / pharmacology*

Substances

Enzyme Inhibitors
Phosphoinositide-3 Kinase Inhibitors
Platelet Aggregation Inhibitors
Triazines