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Peer-reviewedCC BY 4.0eLife

A GCN1-independent activator of the kinase GCN2

  • JiaYi Zhu1
  • Giulia Emanuelli1
  • Glenn Robert Masson2
  • Vanessa Vinciauskaite2
  • Henriette Willems3
  • Peiqiao Cai1
  • Andrew Lim3
  • Christopher Alan Brown3
  • David Winpenny3
  • Murray Clarke4
  • Rebecca Gilley5
  • Fergus Preston6
7 more authors
  • Jordan CJ Wilson7
  • Aldo Bader7
  • Taufiq Rahman8
  • Joseph E Chambers1
  • John Skidmore3
  • Nicholas W Morrell4,9
  • Stefan J Marciniak1,4,9
9 affiliations
  1. 1Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, United Kingdom
  2. 2Division of Cancer Research, School of Medicine, Ninewells Hospital, Dundee, United Kingdom
  3. 3The ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge, United Kingdom
  4. 4Department of Medicine, University of Cambridge, Cambridge, United Kingdom
  5. 5Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
  6. 6Domainex Ltd, Churchill Building, Chesterford Research Park, Saffron Walden, United Kingdom
  7. 7Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
  8. 8Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
  9. 9Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
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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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Cite

BibTeXRIS
BibTeX
@article{zhu2026gcn1independent,
  title = {{A GCN1-independent activator of the kinase GCN2}},
  author = {JiaYi Zhu and Giulia Emanuelli and Glenn Robert Masson and Vanessa Vinciauskaite and Henriette Willems and Peiqiao Cai and Andrew Lim and Christopher Alan Brown and David Winpenny and Murray Clarke and Rebecca Gilley and Fergus Preston and Jordan CJ Wilson and Aldo Bader and Taufiq Rahman and Joseph E Chambers and John Skidmore and Nicholas W Morrell and Stefan J Marciniak},
  journal = {eLife},
  year = {2026},
  month = oct,
  doi = {10.7554/elife.108590},
  url = {https://elifesciences.org/articles/108590},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A GCN1-independent activator of the kinase GCN2
AU  - JiaYi Zhu
AU  - Giulia Emanuelli
AU  - Glenn Robert Masson
AU  - Vanessa Vinciauskaite
AU  - Henriette Willems
AU  - Peiqiao Cai
AU  - Andrew Lim
AU  - Christopher Alan Brown
AU  - David Winpenny
AU  - Murray Clarke
AU  - Rebecca Gilley
AU  - Fergus Preston
AU  - Jordan CJ Wilson
AU  - Aldo Bader
AU  - Taufiq Rahman
AU  - Joseph E Chambers
AU  - John Skidmore
AU  - Nicholas W Morrell
AU  - Stefan J Marciniak
PY  - 2026
DA  - 2026/10/27
JO  - eLife
DO  - 10.7554/elife.108590
UR  - https://elifesciences.org/articles/108590
AB  - 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.
SN  - 2050-084X
ER  -