Background:

AKT-IN-1 is an allosteric AKT inhibitor with an IC50 of 1.042 μM.

AKT-IN-1 is able to potently inhibit phosphorylation of AKT in cells at both Thr308 and Ser473, with IC50s of 0.422 and 0.322 μM, respectively. AKT-IN-1 inhibits the phosphorylation of ribosomal protein S6, a downstream effector of the PI3K-AKT pathway. AKT-IN-1 potently inhibits the phosphorylation of PRAS40[1].

The effects of AKT-IN-1 (Compound 26) in vivo are characterized by measuring the pharmacodynamic activity of AKT-IN-1 in a BT474c breast adenocarcinoma xenograft model. Following acute doses of 100 and 200 mg/kg, AKT-IN-1 potently inhibits the phosphorylation of its downstream substrate GSK3β as well as the phosphorylation of AKT (Ser473), with a potency consistent with its pharmacokinetic profile. The in vivo activity of AKT-IN-1 is further characterized by measuring the effects on the growth of tumor cell xenografts. Continuous (daily) oral dosing of AKT-IN-1 (100 and 200 mg/kg) to nude mice bearing BT474c breast adenocarcinoma xenografts results in inhibition of tumor growth in a dose-dependent manner. When dosed at 200 mg/kg daily, AKT-IN-1 causes significant tumor growth inhibition[1].

[1]. Kettle JG, et al. Diverse heterocyclic scaffolds as allosteric inhibitors of AKT. J Med Chem. 2012 Feb 9;55(3):1261-73.