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

Szu-Yu Kuo, Adam B Castoreno, Leslie N Aldrich, Kara G Lassen, Gautam Goel, Vlado Dančík, Petric Kuballa, Isabel Latorre, Kara L Conway, Sovan Sarkar, Dorothea Maetzel, Rudolf Jaenisch, Paul A Clemons, Stuart L Schreiber, Alykhan F Shamji, Ramnik J Xavier

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)E4281-E4287
JournalNational Academy of Sciences. Proceedings
Volume112
Issue number31
DOIs
Publication statusPublished - 4 Aug 2015

Keywords

  • Autophagy
  • Bacteria
  • Carrier Proteins
  • Cell Aggregation
  • Genetics, Medical
  • Green Fluorescent Proteins
  • HeLa Cells
  • High-Throughput Screening Assays
  • Humans
  • Induced Pluripotent Stem Cells
  • Interleukin-1beta
  • Membrane Glycoproteins
  • Models, Biological
  • Neurons
  • Niemann-Pick Disease, Type C
  • Peptides
  • Phenotype
  • Small Molecule Libraries

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