2. Academic Validation
  3. Discovery of Isohexide Bisglycolamides as Inhibitors of the Integrated Stress Response

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

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.

Figures
Products