AZD8186 is a potent, isoform-specific PI3Kβ inhibitor with IC50 of 4 nM, also inhibits PI3Kδ (IC50=12 nM) with selectivity over PI3Kα (IC50=35 nM) and PI3Kγ (IC50=675 nM); inhibits ADP-induced human platelet aggregation with IC50 of 186 nM, shows no significant binding to 442 other kinases; inhibits PI3Kβ-dependent activation of pAKT (Ser473) in MDA-MB-468 cells (IC50=3 nM), inhibits proliferation of MDA-MB-468 cells (GI50=65 nM); suppresses phosphorylation of AKT, PRAS40, S6, and FOXO with IC50 of 100-fold versus 74 protein and lipid kinases. At 10 μM, AZD8186 had no significant binding to 442 other kinases in a KinomeScan screen. AZD8186 shows selectivity for PI3K family kinases, no other off-target activity is detected. In the PTEN-null line, MDA-MB-468 AZD8186 inhibits PI3Kβ-dependent activation of pAKT (Ser473) with an IC50 value of 3 nM. Potency in the PIK3CA-mutant line BT474c is 752 nM demonstrating selectivity for PI3Kβ over PI3Kα. IgM mediated stimulation of B cells results in phosphorylation of AKT through activation of PI3Kδ. AZD8186 inhibits IgM-stimulated phosphorylation of pAKT (Ser473) activation in JEKO cells with an IC50 value of 17 nM. In cell proliferation assays, AZD8186 inhibits proliferation of MDA-MB-468 cells with a GI50 value of 65 nM, IgM stimulated JEKO cell growth with an IC50 value of 228 nM. It only inhibited BT474c cell growth with an IC50 value of 1.981 μM consistent with its selectivity for PI3Kβ over PI3Kα.\n(In Vivo):To assess single-agent efficacy of AZD8186 in vivo, antitumor activity is assessed in the PTEN-null TNBC models HCC70 and MDA-MB-468, and the prostate models PC3 and HID28. At 50 and 25 mg/kg twice a day, AZD8186 inhibits the growth of all four models. At 25 and 50 mg/kg, HCC70 is inhibited at 62% (P<0.001) and 85% (P<0.001), respectively, MDA-MB-468 is inhibited at 47% (P<0.001) and 76% (P<0.001), respectively, at end at of study, with regression early in the study. Efficacy in the PTEN-null prostate model, PC3 is less pronounced with 25 and 50 mg/kg giving maximal growth inhibition of 59% (P<0.001) and 64% (P<0.001), respectively. In contrast, AZD8186 gives 79% (P<0.001) growth inhibition in the PTEN-null prostate explant model HID28. In mouse, AZD8186 has a short half-life delivering a PK profile that results in intermittent cover over a 24 hours dosing interval. To increase the time of exposure, animals bearing PC3 tumors are co-dosed with AZD8186 in the presence of the Cyt P450 inhibitor ABT, which results in significantly increased exposure. This also increased the efficacy in the PC3 model with 86% (P<0.005) reduction in tumor growth achieved with 30 mg/kg AZD8186+ABT.
