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Hydroxybenzamide derivatives protect pancreatic β cell by suppressing unfolded protein response activation

Venkateswararao Eeda1, Komal N Rawal1, H Greg Matlock2

  • 1Division of Endocrinology, Department of Medicine, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA.

Chemical Biology & Drug Design
|May 26, 2022
PubMed

Insights

Researchers developed new hydroxybenzamide derivatives to protect pancreatic beta cells from endoplasmic reticulum stress, a key factor in diabetes. The compound WO3i shows significant promise for diabetes drug development by protecting beta cells.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Endocrinology

Background:

  • Endoplasmic reticulum (ER) stress is implicated in pancreatic beta cell dysfunction and death, contributing to diabetes development.
  • Existing protective agents against ER stress have limitations, such as a narrow activity range.

Purpose of the Study:

  • To design and synthesize novel hydroxybenzamide (HBA) derivatives as potential beta cell protectants.
  • To identify compounds effective against ER stress-induced beta cell damage.

Main Methods:

  • Synthesis of a series of HBA derivatives with an amide linker replacing a triazole pharmacophore.
  • Structure-activity relationship (SAR) studies to identify potent compounds.
  • Assessment of beta cell protective activity against ER stress and measurement of EC50 values.
  • Analysis of the effects of lead compounds on key apoptotic mediators (CHOP) and unfolded protein response (UPR) pathways (ATF6, IRE1α, PERK).

Main Results:

  • The HBA derivative WO3i demonstrated significant beta cell protective activity against ER stress, with 100% maximal activity and an EC50 of 0.19 μM.
  • WO3i was found to suppress the expression of C/EBP homologous protein (CHOP), a critical mediator of ER stress-induced apoptosis.
  • WO3i effectively inhibited the activation of all three major UPR pathways: ATF6, IRE1α, and PERK.

Conclusions:

  • WO3i represents a novel and potent scaffold for protecting pancreatic beta cells from ER stress.
  • This discovery offers a promising new direction for the development of therapeutic agents for diabetes treatment.
Keywords:
CHOPER stressdiabetespancreatic β cellunfolded protein response

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