A small molecule UPR modulator for diabetes identified by high throughput screening

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• The unfolded protein response (UPR) is a critical cellular pathway originating in the endoplasmic reticulum (ER) to manage misfolded proteins.
• UPR activation enhances chaperone synthesis, protein degradation, and reduces global protein synthesis to restore ER homeostasis.
• Dysregulation of UPR and ER stress are implicated in various metabolic diseases.

Purpose of the Study:

• To identify small molecules that modulate the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress.
• To characterize a novel compound's effect on protein folding and cellular function in disease models.

Main Methods:

• Utilized an ultra-high throughput screening (uHTS) assay employing asialoglycoprotein receptor 1 (ASGR) fused with Cypridina luciferase (CLuc) to measure protein folding capacity.
• Screened a library of one million small molecules to identify modulators of ER stress.
• Evaluated the efficacy of the identified compound (APC655) in cellular assays and in the leptin-deficient (ob/ob) mouse model.

Main Results:

• Identified APC655 as a potent activator of protein folding, likely by promoting chaperone expression.
• APC655 enhanced pancreatic beta cell viability and insulin secretion under ER stress conditions.
• APC655 improved beta cell function and reduced hepatic lipid accumulation in ob/ob mice.

Conclusions:

• A successful uHTS campaign identified APC655, a novel UPR modulator.
• APC655 demonstrates therapeutic potential for metabolic diseases characterized by ER stress.
• This compound represents a promising candidate for further drug development.