AKT is a pivotal component of the PI3K/AKT/mTOR pathway, attracting significant interest as a therapeutic target for cancer. Herein we describe the discovery of a pan-AKT and AKT1-E17K allosteric inhibitor, ARQ 092. The series of novel derivatives of the core scaffold 3<i>H</i>-imidazo[4,5-<i>b</i>]pyridine was first identified through biochemical and biophysical screening assays. A lead optimization campaign provided several highly potent allosteric AKT inhibitors, of which ARQ 092 emerged. ARQ 092 demonstrated potent and sustained inhibition of AKT activation and downstream targets including PRAS40 signaling in cancer cells. PK/PD studies demonstrated its effectiveness at inhibiting the AKT phosphorylation as well as additional downstream effectors following oral dosing in mice. ARQ 092 showed strong tumor growth inhibition in a human xenograft mouse model of PI3K/AKT driven endometrial adenocarcinoma. Co-crystallization studies with unphosphorylated form of AKT1 revealed an allosteric binding mode of ARQ 092 and highlighted the role of the key cyclobutyl amine moiety that is critical for pharmacological activity.

Discovery of ARQ 092: A potent, selective allosteric inhibitor of AKT1, 2, 3 and AKT1-E17K in clinical development for cancer and rare diseases

253rd National Meeting (2017)

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