Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 31, Pages E4281-E4287Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1512289112
Keywords
high-throughput screening; autophagy; small-molecule probes; Crohn's disease
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Funding
- Leona M. and Harry B. Helmsley Charitable Trust Grant [500203]
- National Institute of Allergy and Infectious Diseases' Center for Excellence in Translational Research Grant [U19AI109725]
- Birmingham Fellowship
- National Niemann-Pick Disease Foundation Foundation
- Skoltech Center
- NIH [DK097485, U01CA176152, R01-NS088538, MH104610]
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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.
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