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Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

Author(s)
Kuo, Szu-Yu; Castoreno, Adam B.; Aldrich, Leslie N.; Lassen, Kara G.; Goel, Gautam; Dancik, Vlado; Kuballa, Petric; Latorre, Isabel; Conway, Kara L.; Sarkar, Sovan; Maetzel, Dorothea; Jaenisch, Rudolf; Clemons, Paul A.; Schreiber, Stuart L.; Shamji, Alykhan F.; Xavier, Ramnik J.; ... Show more Show less
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Abstract
Studies of human genetics and pathophysiology have implicated the regulation of autophagy in inflammation, neurodegeneration, infection, and autoimmunity. These findings have motivated the use of small-molecule probes to study how modulation of autophagy affects disease-associated phenotypes. Here, we describe the discovery of the small-molecule probe BRD5631 that is derived from diversity-oriented synthesis and enhances autophagy through an mTOR-independent pathway. We demonstrate that BRD5631 affects several cellular disease phenotypes previously linked to autophagy, including protein aggregation, cell survival, bacterial replication, and inflammatory cytokine production. BRD5631 can serve as a valuable tool for studying the role of autophagy in the context of cellular homeostasis and disease.
Date issued
2015-08
URI
http://hdl.handle.net/1721.1/101110
Department
Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Kuo, Szu-Yu, Adam B. Castoreno, Leslie N. Aldrich, Kara G. Lassen, Gautam Goel, Vlado Dancik, Petric Kuballa, et al. “Small-Molecule Enhancers of Autophagy Modulate Cellular Disease Phenotypes Suggested by Human Genetics.” Proc Natl Acad Sci USA 112, no. 31 (July 20, 2015): E4281–E4287.
Version: Final published version
ISSN
0027-8424
1091-6490

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