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. Epub 2015 Jul 20.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / drug effects*
  • Bacteria / drug effects
  • Carrier Proteins / metabolism
  • Cell Aggregation / drug effects
  • Genetics, Medical*
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • High-Throughput Screening Assays
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Interleukin-1beta / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / metabolism
  • Models, Biological
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Niemann-Pick C1 Protein
  • Niemann-Pick Disease, Type C / genetics*
  • Niemann-Pick Disease, Type C / metabolism
  • Niemann-Pick Disease, Type C / pathology*
  • Peptides / metabolism
  • Phenotype
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*


  • Carrier Proteins
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • Niemann-Pick C1 Protein
  • Peptides
  • Small Molecule Libraries
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • polyglutamine