title: Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics.
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.
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138;
authors.forename: Szu-Yu
authors.initials: SY
authors.lastname: Kuo
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
authors.forename: Adam B
authors.initials: AB
authors.lastname: Castoreno
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138;
authors.forename: Leslie N
authors.initials: LN
authors.lastname: Aldrich
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142;
authors.forename: Kara G
authors.initials: KG
authors.lastname: Lassen
authors.affiliation: 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;
authors.forename: Gautam
authors.initials: G
authors.lastname: Goel
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
authors.forename: Vlado
authors.initials: V
authors.lastname: Dančík
authors.affiliation: 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;
authors.forename: Petric
authors.initials: P
authors.lastname: Kuballa
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
authors.forename: Isabel
authors.initials: I
authors.lastname: Latorre
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142;
authors.forename: Kara L
authors.initials: KL
authors.lastname: Conway
authors.affiliation: 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;
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142;
authors.forename: Dorothea
authors.initials: D
authors.lastname: Maetzel
authors.affiliation: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142; Skolkovo Institute of Science and Technology (Skoltech), Skolkovo 143025, Moscow Region, Russia;
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: 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.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; stuart_schreiber@harvard.edu ashamji@broadinstitute.org xavier@molbio.mgh.harvard.edu.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: 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.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D001419:Bacteria / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002449:Cell Aggregation / Q000187:drug effects; D005826:Genetics, Medical; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D010455:Peptides; D054852:Small Molecule Libraries; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C097188:polyglutamine
keywords: Crohn’s disease; autophagy; high-throughput screening; small-molecule probes