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

Gregory B. Craven, Hang Chu, Jessica D. Sun, Jordan D. Carelli, Brittany Coyne, Hao Chen, Ying Chen, Xiaolei Ma, Subhamoy Das, Wayne Kong, Adam D. Zajdlik, Kin S. Yang, Solomon H. Reisberg, Peter A. Thompson, J. Russell Lipford and Jack Taunton ()
Additional contact information
Gregory B. Craven: University of California, San Francisco
Hang Chu: Terremoto Biosciences
Jessica D. Sun: Terremoto Biosciences
Jordan D. Carelli: Terremoto Biosciences
Brittany Coyne: Terremoto Biosciences
Hao Chen: University of California, San Francisco
Ying Chen: University of California, San Francisco
Xiaolei Ma: Terremoto Biosciences
Subhamoy Das: Terremoto Biosciences
Wayne Kong: Terremoto Biosciences
Adam D. Zajdlik: Terremoto Biosciences
Kin S. Yang: Terremoto Biosciences
Solomon H. Reisberg: Terremoto Biosciences
Peter A. Thompson: Terremoto Biosciences
J. Russell Lipford: Terremoto Biosciences
Jack Taunton: University of California, San Francisco

Nature, 2025, vol. 637, issue 8044, 205-214

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-024-08176-4

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