Afuresertib

A potent, selective, ATP-competitive pan-AKT inhibitor with biochemical IC50 of 0.08/2/2.6 nM for AKT1/2/3; also inhibits PKA (IC50=1.3 nM) and AKT1 E17K mutant (IC50=0.2 nM), selective over PKC, PKG isoforms and p70S6K; orally bioactive.Gastric Cancer Phase 1 Discontinued (In Vitro) :Afuresertib (GSK2110183) exhibits favorable tumor-suppressive effects on malignant pleural mesothelioma (MPM) cells. Afuresertib significantly increases caspase-3 and caspase-7 activities and apoptotic cell number among ACC-MESO-4 and MSTO-211H cells. Afuresertib strongly arrests the cell cycle in the G1 phase. Western blotting analysis shows that Afuresertib increases the expression of p21WAF1/CIP1 and decreases the phosphorylation of Akt substrates, including GSK-3β and FOXO family proteins. Afuresertib-induced p21 expression promotes G1 phase arrest by inducing FOXO activity. Afuresertib significantly enhances cisplatin-induced cytotoxicity. Afuresertib modulates the expression E2F1 and MYC, which are associated with fibroblast core serum response. (In Vivo) :Mice bearing BT474 breast tumor xenografts are dosed orally with either vehicle or GSK2110183 at 10, 30 or 100 mg/kg daily for 21 days which result in 8, 37 and 61% TGI, respectively. Mice tolerated GSK2110183 well, with 1-3% body weight loss reported after 5 days of dosing which recover over the course of the study. Other tumor xenograft models which possess an activation of the Akt pathway are explored to further demonstrate compound efficacy. Mice treated with GSK2110183 at 10, 30 and 100 mg/kg result in 23, 37 and 97% TGI, respectively, of SKOV3 xenografts.