2. Academic Validation
  3. Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

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

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 stuart_schreiber@harvard.edu ashamji@broadinstitute.org xavier@molbio.mgh.harvard.edu.
  • 10 Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; stuart_schreiber@harvard.edu ashamji@broadinstitute.org xavier@molbio.mgh.harvard.edu.
  • 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; stuart_schreiber@harvard.edu ashamji@broadinstitute.org xavier@molbio.mgh.harvard.edu.
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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