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Design, Synthesis, and Cellular Efficacy of Inositol-Requiring Enzyme Type 1 (IRE1α) Inhibitors.

Giulia Murbach1, Adam D Mitrevski2, Patricia A Fontan3

  • 1Department of Chemistry, Multidisciplinary Cancer Research Facility, Purdue University, 1203 W. State Street, West Lafayette, Indiana 47907, United States.

ACS Medicinal Chemistry Letters
|November 19, 2025
PubMed
Summary

Researchers designed novel small molecules targeting IRE1α (inositol-requiring enzyme 1 alpha) for ER stress. Six compounds showed potent IRE1α inhibition, with three exhibiting superior efficacy and safety profiles compared to existing standards.

Keywords:
ARPE-19DESI-MSDoEER stressHTEIRE1α inhibitorsKIRA6Molecular dockingSuzuki coupling

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Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Endoplasmic reticulum (ER) stress is implicated in various diseases.
  • IRE1α (inositol-requiring enzyme 1 alpha) is a key mediator of the unfolded protein response (UPR) and a therapeutic target.
  • Developing selective IRE1α inhibitors is crucial for treating ER stress-related conditions.

Purpose of the Study:

  • To design and synthesize a novel library of small molecules targeting IRE1α.
  • To evaluate the inhibitory potential and therapeutic efficacy of these compounds in cellular models of ER stress.

Main Methods:

  • Molecular docking was employed to design 66 small molecule candidates.
  • A two-step synthesis involving Suzuki coupling and carbamoylation was utilized.
  • High-throughput experimentation (HTE) and a 3^3 Design of Experiments (DoE) approach optimized the Suzuki coupling.
  • Compounds were screened in a tunicamycin-induced ER stress assay using ARPE-19 cells.
  • Kinase inhibition was quantified by RT-qPCR, and IC50 values were determined.

Main Results:

  • 14 derivatives showed potential for IRE1α inhibition.
  • Six compounds exhibited IRE1α inhibition comparable to the standard KIRA6.
  • Three lead compounds demonstrated improved IC50 values.
  • The most effective inhibitors were non-cytotoxic at working concentrations and offered enhanced protection against apoptosis.

Conclusions:

  • A novel library of IRE1α inhibitors was successfully synthesized and optimized.
  • Several potent and selective IRE1α inhibitors with improved therapeutic profiles were identified.
  • These findings provide promising leads for the development of new therapeutics for ER stress-related diseases.