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Sci Transl Med. 2015 Jun 17;7(292):292ra98. doi: 10.1126/scitranslmed.aaa9134.

Phenotypic assays identify azoramide as a small-molecule modulator of the unfolded protein response with antidiabetic activity.

Author information

1
Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. School of Life Sciences, Tsinghua University, Peking-Tsinghua Center for Life Sciences, Beijing 100084, China.
2
Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
3
Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ghotamis@hsph.harvard.edu.

Abstract

The endoplasmic reticulum (ER) plays a critical role in protein, lipid, and glucose metabolism as well as cellular calcium signaling and homeostasis. Perturbation of ER function and chronic ER stress are associated with many pathologies ranging from diabetes and neurodegenerative diseases to cancer and inflammation. Although ER targeting shows therapeutic promise in preclinical models of obesity and other pathologies, the available chemical entities generally lack the specificity and other pharmacological properties required for effective clinical translation. To overcome these challenges and identify new potential therapeutic candidates, we first designed and chemically and genetically validated two high-throughput functional screening systems that independently measure the free chaperone content and protein-folding capacity of the ER. With these quantitative platforms, we characterized a small-molecule compound, azoramide, that improves ER protein-folding ability and activates ER chaperone capacity to protect cells against ER stress in multiple systems. This compound also exhibited potent antidiabetic efficacy in two independent mouse models of obesity by improving insulin sensitivity and pancreatic β cell function. Together, these results demonstrate the utility of this functional, phenotypic assay platform for ER-targeted drug discovery and provide proof of principle for the notion that specific ER modulators can be potential drug candidates for type 2 diabetes.

PMID:
26084805
PMCID:
PMC5063051
DOI:
10.1126/scitranslmed.aaa9134
[Indexed for MEDLINE]
Free PMC Article

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