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

  • Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4281-7. doi: 10.1073/pnas.1512289112.
Szu-Yu Kuo  1 ,  Adam B Castoreno  2 ,  Leslie N Aldrich  3 ,  Kara G Lassen  4 ,  Gautam Goel  5 ,  Vlado Dančík  2 ,  Petric Kuballa  5 ,  Isabel Latorre  2 ,  Kara L Conway  4 ,  Sovan Sarkar  6 ,  Dorothea Maetzel  7 ,  Rudolf Jaenisch  8 ,  Paul A Clemons  2 ,  Stuart L Schreiber  9 ,  Alykhan F Shamji  10 ,  Ramnik J Xavier  11
Affiliations
  • 1. Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138;
  • 2. Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
  • 3. Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138;
  • 4. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142;
  • 5. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114;
  • 6. Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142; Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
  • 7. Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142;
  • 8. Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142; Skolkovo Institute of Science and Technology (Skoltech), Skolkovo 143025, Moscow Region, Russia;
  • 9. Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; Howard Hughes Medical Institute, Cambridge, MA 02142 [email protected] [email protected] [email protected].
  • 10. Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; [email protected] [email protected] [email protected].
  • 11. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114; [email protected] [email protected] [email protected].
PMID: 26195741 DOI: 10.1073/pnas.1512289112
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.

Keywords
Crohn’s disease; autophagy; high-throughput screening; small-molecule probes.
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