2. Academic Validation
  3. A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response

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

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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