A GCN1-independent activator of the kinase GCN2

Abstract Mutations of EIF2AK4, which encodes the eIF2α kinase GCN2, cause a severe inherited form of pulmonary hypertension called pulmonary veno-occlusive disease (PVOD). Some pathogenic variants of GCN2 are amenable to pharmacological reactivation by low concentrations of ATP-pocket binding inhibitors. Kinase inhibition at modestly elevated concentrations limits the clinical utility of these drugs against PVOD. We therefore performed an in cellulo chemical screen for GCN2 activators and identified three structurally distinct compounds with low micromolar stimulatory activities. Unlike previously described GCN2 activators, one of these molecules activated GCN2 independently of GCN1. Modelling supported by structure activity screens suggested it binds within the ATP-pocket of GCN2, but unlike existing ligands does not protrude inward into the allosteric pocket or outward into the solvent. This overcomes a key requirement of other GCN2 activators.

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Publication Details

Journal
eLife
Published
2025-09-26
DOI
https://doi.org/10.7554/elife.108590
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
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article

A GCN1-independent activator of the kinase GCN2

Christopher C. Brown, Joseph E. Chambers, Aldo S. Bader, Henriëtte M. G. Willems et al.
eLife
Endoplasmic Reticulum Stress and Disease
article

A GCN1-independent activator of the kinase GCN2

Christopher C. Brown, Joseph E. Chambers, Aldo S. Bader, Henriëtte M. G. Willems, Nicholas W. Morrell, Tariq Rahman, Rebecca Gilley, Giulia Emanuelli, Vanesa Vinciauskaite, Jordan Wilson, Glenn R. Masson, David Winpenny, Anthony C.B. Lim, Stefan John Marciniak, John Skidmore, Jiayi Zhu, M Clarke, F. W. Preston
article en

Abstract

Abstract Mutations of EIF2AK4, which encodes the eIF2α kinase GCN2, cause a severe inherited form of pulmonary hypertension called pulmonary veno-occlusive disease (PVOD). Some pathogenic variants of GCN2 are amenable to pharmacological reactivation by low concentrations of ATP-pocket binding inhibitors. Kinase inhibition at modestly elevated concentrations limits the clinical utility of these drugs against PVOD. We therefore performed an in cellulo chemical screen for GCN2 activators and identified three structurally distinct compounds with low micromolar stimulatory activities. Unlike previously described GCN2 activators, one of these molecules activated GCN2 independently of GCN1. Modelling supported by structure activity screens suggested it binds within the ATP-pocket of GCN2, but unlike existing ligands does not protrude inward into the allosteric pocket or outward into the solvent. This overcomes a key requirement of other GCN2 activators.

eLife
Babraham Institute (GB), University of Cambridge (GB), Cancer Research UK (GB), Ninewells Hospital (GB), Papworth Hospital NHS Foundation Trust (GB), Domainex (United Kingdom) (GB), Drug Discovery Laboratory (Norway) (NO)
Openalex Percentile: Top 72%
Endoplasmic Reticulum Stress and Disease
DOIOpen Access PDFOpenAlex
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