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Published on: November 15, 2013
Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation
Gregory B Craven1, Hang Chu2, Jessica D Sun2
1Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
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.
Insights
Researchers developed a novel inhibitor targeting the AKT1 (E17K) mutation, a common driver in many cancers. This mutant-selective approach avoids hyperglycemia side effects seen with other AKT inhibitors, offering a promising new cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Somatic alterations in the AKT1 kinase, particularly the E17K mutation, are prevalent in various solid tumors.
- The AKT1 E17K mutation leads to constitutive signaling, driving oncogenesis.
- Existing pan-AKT inhibitors cause dose-limiting hyperglycemia, necessitating the development of mutant-selective inhibitors.
Purpose of the Study:
- To design and develop novel, mutant-selective inhibitors targeting the AKT1 E17K mutation.
- To overcome the challenge of achieving selectivity over wild-type AKT paralogs.
- To explore a new therapeutic strategy for AKT1 (E17K)-driven cancers.
Main Methods:
- Design of allosteric, lysine-targeted salicylaldehyde inhibitors.
- Crystallographic analysis of inhibitor-kinase complexes.
- In vitro and in vivo evaluation in AKT1 (E17K) xenograft models.
- Assessment of Zn2+ recruitment and inhibition in cellular models.
Main Results:
- Developed salicylaldehyde inhibitors with selectivity for AKT1 (E17K).
- Discovered unexpected Zn2+ chelation by the inhibitor-kinase adduct, enhancing sustained inhibition.
- Demonstrated efficacy in AKT1 (E17K) tumor xenografts without inducing hyperglycemia.
- Achieved exquisite residence-time-based selectivity by targeting the mutant lysine and Zn2+ chelation.
Conclusions:
- Targeting the AKT1 E17K mutant lysine with salicylaldehyde inhibitors, coupled with Zn2+ chelation, offers a highly selective approach.
- This strategy provides a potential therapeutic window for treating AKT1 (E17K)-driven cancers without dose-limiting hyperglycemia.
- The findings highlight a novel mechanism for achieving mutant-specific kinase inhibition.
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