Discovery of Isohexide Bisglycolamides as Inhibitors of the Integrated Stress Response

ACS Medicinal Chemistry Letters 2026 Open access

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Authors: Vincent J. Colandrea, Amruta Joshi‐Pangu, Robert T. Nolte, Randy K. Bledsoe, Paris Ward, Jack Glancy, Matthew D. Kowalski, Chelsea A. Huff, Sapna Desai, Rakesh Nagilla, Nicholas J. Laping, Jeffrey M. Axten
+1 more Karen Anderson Evans
DOI: 10.1021/acsmedchemlett.5c00698
Cited by: 1
References: 26

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.

Fields of Study & Subjects

Redox biology and oxidative stress Endoplasmic Reticulum Stress and Disease RNA regulation and disease

Publication details

Journal / source
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society (ACS)
Volume
17
Issue
2
Pages
495–502
Publication date
15 January 2026
Language
EN