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

Xufen Yu, Jia Xu, Kaitlyn M. Cahuzac, Ling Xie, Yudao Shen, Xian Chen, Jing Liu, Ramon E. Parsons, Jian Jin

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)14237-14260
Number of pages24
JournalJournal of Medicinal Chemistry
Volume65
Issue number20
DOIs
StatePublished - 27 Oct 2022

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