Discovery of Isohexide Bisglycolamides as Inhibitors of the Integrated Stress Response

  • ACS Med Chem Lett. 2026 Jan 15;17(2):495-502. doi: 10.1021/acsmedchemlett.5c00698.
Vincent J Colandrea  1 ,  Amruta Joshi-Pangu  1 ,  Robert T Nolte  2 ,  Randy K Bledsoe  2 ,  Paris Ward  2 ,  Jack Glancy  3 ,  Matthew D Kowalski  1 ,  Chelsea A Huff  1 ,  Sapna Desai  4 ,  Rakesh Nagilla  5 ,  Nicholas J Laping  6 ,  Jeffrey M Axten  1 ,  Karen A Evans  1
Affiliations
  • 1. Discovery Chemistry, GSK, 1250 S Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 2. Protein Cellular and Structural Sciences, GSK, Collegeville, Pennsylvania 19426, United States.
  • 3. Molecular Design, GSK, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
  • 4. Discovery Biology and Screening, GSK, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
  • 5. Discovery DMPK, GSK, Collegeville, Pennsylvania 19426, United States.
  • 6. Discovery Biology, GSK, Collegeville, Pennsylvania 19426, United States.
PMID: 41704357 DOI: 10.1021/acsmedchemlett.5c00698
Abstract

ISRIB reactivates protein synthesis for cells under stress through the stabilization of eukaryotic initiation factor 2 beta (eIF2B). We discovered that diaminoisohexides, derived from isomannide and isosorbide serve as a bioisostere for the diamino cyclohexane core in ISRIB. These scaffolds conferred improved solubility but also showed activity for the human ether-a-go-go-related gene (hERG). Herein we describe our efforts to mitigate hERG activity while maintaining target potency. The first high resolution (2.25Å) X-ray cocrystal structure of the eIF2B (α,β,δ)2 complex with compound 7a is reported, which can inform subsequent SAR.

Keywords
ISRIB; eIF2B; hERG; integrated stress response; isomannide; isosorbide.
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