Novel Allosteric Inhibitor-Derived AKT Proteolysis Targeting Chimeras (PROTACs) Enable Potent and Selective AKT Degradation in KRAS/BRAF Mutant Cells

AKT is an important target for cancer therapeutics. Significant
advancements have been made in developing ATP-competitive and allosteric
AKT inhibitors. Recently, several AKT proteolysis targeting chimeras
(PROTACs) derived from ATP-competitive AKT inhibitors have been reported,
including MS21. While MS21 potently degraded AKT and inhibited the
growth in tumor cells harboring PI3K/PTEN pathway mutation, it was
largely ineffective in degrading AKT in KRAS/BRAF mutated cells as
a single agent. To overcome the AKT degradation resistance in KRAS/BRAF
mutated cells, we developed novel AKT PROTACs derived from an AKT
allosteric inhibitor, including degrader 62 (MS15). 62 displayed potent and selective AKT degradation activity
and potent antiproliferative activity in KRAS/BRAF mutated cancer
cells, in addition to PI3K/PTEN mutated cancer cells. Furthermore, 62 was bioavailable in mice through intraperitoneal administration.
Overall, 62 is a valuable chemical tool to degrade AKT
in cells harboring KRAS/BRAF mutation and expands the tool box for
pharmacologically modulating AKT.