Pharmacological targeting of the unfolded protein response for disease intervention

• Published in: Nature chemical biology Vol. 15; no. 8; pp. 764 - 775
• Main Authors: Hetz, Claudio, Axten, Jeffrey M., Patterson, John B.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-08-2019; Nature Publishing Group
• Subjects: 631/154; 631/92/470; Animals; Apoptosis; Beta cells; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Brain; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Cholesterol; Design optimization; Diabetes mellitus; Disease; Drug Delivery Systems; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; Humans; Lipids; Liver; Liver cancer; Liver diseases; Lymphocytes; Metabolic disorders; Metabolic syndrome; Neoplasms - drug therapy; Neoplasms - metabolism; Neurodegeneration; Pancreas; Pharmacology; Protein folding; Proteins; Review Article; Signal Transduction; Signaling; Solid tumors; Unfolded Protein Response
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-019-0326-2

Accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a salient attribute of many human diseases including obesity, liver disorders, cancer, diabetes and neurodegeneration. To restore ER proteostasis, cells activate the unfolded protein response (UPR), a signaling pathway that imposes adaptive programs or triggers apoptosis of damaged cells. The UPR is critical to sustain the normal function of specialized secretory cells (i.e., pancreatic β cells and B lymphocytes) and to control the production of lipids and cholesterol in the liver. In the context of disease, adaptive UPR responses have been linked to the growth of solid tumors, whereas chronic ER stress contributes to cell dysfunction in brain diseases, metabolic syndromes, among other conditions. Here we discuss recent developments in the design and optimization of novel compounds to manipulate UPR signaling and their efficacy in various disease models.
Hetz et al. discuss recent advances in the identification and optimization of small molecules targeting the unfolded protein response and the application of these small molecules in cancers, neurodegeneration and metabolic diseases.