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Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4281-7. doi: 10.1073/pnas.1512289112. Epub 2015 Jul 20.

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

Author information

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.

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

PMID:
26195741
PMCID:
PMC4534235
DOI:
10.1073/pnas.1512289112
[Indexed for MEDLINE]
Free PMC Article

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