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

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

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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–activity relationship (SAR) results have been reported. Through extensive SAR studies on various linkers, E3 ligase ligands, and AKT binding moieties, we identified two novel and potent AKT proteolysis targeting chimera (PROTAC) degraders: von Hippel–Lindau (VHL)-recruiting degrader 13 (MS98) and cereblon (CRBN)-recruiting degrader 25 (MS170). These two compounds selectively induced robust AKT protein degradation, inhibited downstream signaling, and suppressed cancer cell proliferation. Moreover, these two degraders exhibited good plasma exposure levels in mice through intraperitoneal injection. Overall, our comprehensive SAR studies led to the discovery of degraders 13 and 25, which are potentially useful chemical tools to investigate biological and pathogenic functions of AKT in vitro and in vivo.

Original languageEnglish
Pages (from-to)18054-18081
Number of pages28
JournalJournal of Medicinal Chemistry
Volume64
Issue number24
DOIs
StatePublished - 23 Dec 2021

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