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.
authors.affiliation: 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.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Pinson
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Mountford
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Prahran, Victoria 3004, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Orive
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Prahran, Victoria 3004, Australia.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Schoenwaelder
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Shackleford
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Powell
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Prahran, Victoria 3004, Australia.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Nelson
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Prahran, Victoria 3004, Australia.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Hamilton
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Prahran, Victoria 3004, Australia.
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Jennings
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: philip.thompson@monash.edu.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D014227:Triazines / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010975:Platelet Aggregation Inhibitors; D014227:Triazines
keywords: Kinase selectivity; PI3 kinase; Platelet aggregation inhibitors; Thrombosis