A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response

  • Nat Commun. 2026 May 6. doi: 10.1038/s41467-026-72688-y.
Fiona Shilliday  #  1 ,  Miguel Gancedo-Rodrigo  #  2 ,  Ginto George  #  3 ,  Shintaro Aibara  2 ,  Santosh Adhikari  2 ,  Syedah Neha Ashraf  2 ,  Evelyne J Barrey  2 ,  Paolo A Centrella  4 ,  Damian Crowther  2 ,  Paige Dickson  4 ,  Diana Gikunju  4 ,  Marie-Aude Guié  4 ,  John P Guilinger  4 ,  Anders Gunnarsson  5 ,  Heather P Harding  3 ,  Christopher D Hupp  4 ,  Rachael Jetson  4 ,  Anthony D Keefe  4 ,  JeeSoo Monica Kim  6 ,  Richard J Lewis  7 ,  Taiana Maia de Oliveira  2 ,  Jennifer Le-Marshall  4 ,  Usha Narayanan  4 ,  Katherine A Nugai  4 ,  Dušan Petrović  5 ,  Emma Rivers  2 ,  David Ron  3 ,  Daisy Stringfellow  6 ,  Karl Syson  2 ,  Lewis Ward  2 ,  John T S Yeoman  4 ,  Yan Yu  4 ,  Ying Zhang  4 ,  Alisa Zyryanova  3 ,  David J Baker  8 ,  Perla Breccia  6 ,  John E Linley  6
Affiliations
  • 1. Discovery Sciences, R&D, AstraZeneca, Cambridge, UK. [email protected].
  • 2. Discovery Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 3. Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK.
  • 4. X-Chem Inc., Waltham, Massachusetts, USA.
  • 5. Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 6. Neuroscience, R&D, AstraZeneca, Cambridge, UK.
  • 7. Department of Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 8. Biologics Engineering, R&D, AstraZeneca, Cambridge, UK.
  • # Contributed equally.
PMID: 42091608 DOI: 10.1038/s41467-026-72688-y
Abstract

Eukaryotic initiation factor 2B (eIF2B), a Guanine Nucleotide exchange factor (GEF), promotes protein synthesis by charging translation initiation factor 2 (eIF2) with GTP. Stress-induced phosphorylation of eIF2 on its α-subunit [eIF2(αP)] inhibits this reaction triggering a protective Integrated Stress Response (ISR). A DNA-encoded chemical library (DEL) screen for modulators of eIF2B, led to the identification of a chemical series that stabilises the inactive state of eIF2B, stimulating the ISR. Cryo-EM of compound-bound eIF2B reveals a conformational switch to the inactive state engaged by eIF2(αP). In cells, compound activity is sensitive to eIF2's phosphorylation state and to a competing eIF2B ligand (ISRIB) that activates the GEF allosterically. These findings establish the feasibility of targeting eIF2B with a drug-like allosteric inhibitor, that serves as an ISR activator (ISRAC), paving the way to explore the therapeutic potential of eIF2B-directed ISR activation.

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