2026/05/06 by Fiona Shilliday, Miguel Gancedo-Rodrigo, Ginto George +33 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Endoplasmic Reticulum Stress and Disease #RNA regulation and disease #PI3K/AKT/mTOR signaling in cancer
paper · doi:10.1038/s41467-026-72688-y
openalex publication_date 2026/05/06 · openalex created_date 2026/05/07 · openalex updated_date 2026/07/27
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. Protein synthesis is tightly regulated by the integrated stress response, but therapeutic activation remains challenging. Here, the authors identify a drug‑like allosteric inhibitor, an ISRAC, that stabilises inactive eIF2B, mimicking stress‑induced eIF2α phosphorylation to activate the ISR, establishing eIF2B as a tractable target for ISR modulation.