Discovery of 3‑(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl‑3<i>H</i>‑imidazo[4,5‑<i>b</i>]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor

The work in this paper describes the optimization of the 3-(3-phenyl-3<i>H</i>-imidazo­[4,5-<i>b</i>]­pyridin-2-yl)­pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (<b>21a</b>). The cocrystal structure of compound <b>21a</b> bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound <b>21a</b> demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound <b>21a</b> also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma