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Beschreibung

A cell-permeable thienopyrimidine compound that acts as a potent, ATP-competitive inhibitor against class IA (IC50 = 3 nM/p110alpha, 33 nM/p110beta, 3 nM/p110delta) & IB (IC50 = 75 nM/p110gamma) PI 3-K kinases, including the two known p110alpha hot spot mutants E454K & H1047R (IC50 = 3 nM), while exhibiting much reduced or little potency against more than 200 other kinases, including TrkA, class II C2beta, class IV mTOR & DNA-PK (IC50 = 2.85, 0.67, 0.58, and 1.23 µ,M, respectively) and class III Vps34 (IC50 >10 µ,M). Effectively inhibits cellular Akt S473 phosphorylation (IC50 = 46 nM/U87MG, 37 nM/PC3, and 28 nM/MDA-MB-361) as well as proliferation in cancer cultures in vitro (GI50 = 950/U87MG, 280/PC3, and 720 nM/MDA-MB-361) and greatly prevents the expansion of U87MG glioblastoma xenograft in mice in vivo (by 83%, 75 mg/kg/d p.o. for 21 days). Oral bioavailability is reported in human, dog, mouse, and rat., A cell-permeable thienopyrimidine compound that acts as a potent, ATP-competitive inhibitor against class IA (IC50 = 3 nM/p110alpha, 33 nM/p110beta, 3 nM/p110delta) & IB (IC50 = 75 nM/p110gamma) PI 3-K kinases, including the two known p110alpha hot spot mutants E454K & H1047R (IC50 = 3 nM), while exhibiting much reduced or little potency against more than 200 other kinases, including TrkA, class II C2beta, class IV mTOR & DNA-PK (IC50 = 2.85, 0.67, 0.58, and 1.23 µ,M, respectively) and class III Vps34 (IC50 >10 µ,M). Effectively inhibits cellular Akt S473 phosphorylation (IC50 = 28 to 46 nM) as well as proliferation in cancer cultures in vitro (GI50 = 280 to 950 nM) and completely prevents the expansion of U87MG glioblastoma xenograft in mice in vivo (by 83%, 75 mg/kg/d p.o. for 21 days). Oral bioavailability is reported in human, dog, mouse, and rat.