Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation

• 成果类型: Article
• 署名作者: Craven, Gregory B.; Chu, Hang; Sun, Jessica D.; Carelli, Jordan D.; Coyne, Brittany; Chen, Hao; Chen, Ying; Ma, Xiaolei; Das, Subhamoy; Kong, Wayne; Zajdlik, Adam D.; Yang, Kin S.; Reisberg, Solomon H.; Thompson, Peter A.; Lipford, J. Russell; Taunton, Jack
• 署名单位: University of California System; University of California San Francisco
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1476
• DOI: 10.1038/s41586-024-08176-4
• 发表日期: 2025-01-02
• 关键词: glucose-homeostasis; peptide identification; akt1(e17k) mutations; insulin-resistance; mice lacking; kinase; GROWTH; tumors; capivasertib; meningiomas

摘要

Somatic alterations in the oncogenic kinase AKT1 have been identified in a broad spectrum of solid tumours. The most common AKT1 alteration replaces Glu17 with Lys (E17K) in the regulatory pleckstrin homology domain1, resulting in constitutive membrane localization and activation of oncogenic signalling. In clinical studies, pan-AKT inhibitors have been found to cause dose-limiting hyperglycaemia2-6, which has motivated the search for mutant-selective inhibitors. We exploited the E17K mutation to design allosteric, lysine-targeted salicylaldehyde inhibitors with selectivity for AKT1 (E17K) over wild-type AKT paralogues, a major challenge given the presence of three conserved lysines near the allosteric site. Crystallographic analysis of the covalent inhibitor complex unexpectedly revealed an adventitious tetrahedral zinc ion that coordinates two proximal cysteines in the kinase activation loop while simultaneously engaging the E17K-imine conjugate. The salicylaldimine complex with AKT1 (E17K), but not that with wild-type AKT1, recruits endogenous Zn2+ in cells, resulting in sustained inhibition. A salicylaldehyde-based inhibitor was efficacious in AKT1 (E17K) tumour xenograft models at doses that did not induce hyperglycaemia. Our study demonstrates the potential to achieve exquisite residence-time-based selectivity for AKT1 (E17K) by targeting the mutant lysine together with Zn2+ chelation by the resulting salicylaldimine adduct. A mutant-selective AKT inhibitor shows potential as a targeted therapy for breast cancer, enabling enhanced target engagement and avoiding the dose-limiting toxicity associated with pan-AKT inhibitors.