Design, Synthesis, and Evaluation of Potent, Selective, and Bioavailable AKT Kinase Degraders

The serine/threonine kinase AKT functions as a critical node of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (m-TOR)signaling pathway. Aberrant activation and overexpression of AKT are strongly correlated with numerous human cancers. To date, only two AKT degraders with no structure & minus;activityrelationship (SAR) results have been reported. Through extensive SAR studies on variouslinkers, E3 ligase ligands, and AKT binding moieties, we identified two novel and potentAKT proteolysis targeting chimera (PROTAC) degraders: von Hippel & minus;Lindau (VHL)-recruiting degrader13(MS98) and cereblon (CRBN)-recruiting degrader25(MS170).These two compounds selectively induced robust AKT protein degradation, inhibiteddownstream signaling, and suppressed cancer cell proliferation. Moreover, these twodegraders exhibited good plasma exposure levels in mice through intraperitoneal injection. Overall, our comprehensive SAR studies led to the discovery of degraders13and25, which are potentially useful chemical tools to investigate biological and pathogenic functions of AKT in vitro and in vivo.

Automated summary

AKT, a critical node in the PI3K/AKT/m-TOR signaling pathway, is strongly correlated with cancer. Two novel and potent AKT degraders were identified, showing the ability to induce AKT protein degradation and inhibit cancer cell proliferation.