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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Autophagy / drug effects*
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Bacteria / drug effects
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Carrier Proteins / metabolism
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Cell Aggregation / drug effects
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Genetics, Medical*
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Green Fluorescent Proteins / metabolism
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HeLa Cells
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High-Throughput Screening Assays
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Humans
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Induced Pluripotent Stem Cells / drug effects
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Induced Pluripotent Stem Cells / metabolism
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Interleukin-1beta / metabolism
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins / metabolism
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Models, Biological
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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Niemann-Pick C1 Protein
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Niemann-Pick Disease, Type C / genetics*
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Niemann-Pick Disease, Type C / metabolism
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Niemann-Pick Disease, Type C / pathology*
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Peptides / metabolism
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Phenotype
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
Substances
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Carrier Proteins
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Interleukin-1beta
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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NPC1 protein, human
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Niemann-Pick C1 Protein
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Peptides
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Small Molecule Libraries
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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polyglutamine