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

SY Kuo, AB Castoreno, LN Aldrich… - Proceedings of the …, 2015 - National Acad Sciences
SY Kuo, AB Castoreno, LN Aldrich, KG Lassen, G Goel, V Dančík, P Kuballa, I Latorre
Proceedings of the National Academy of Sciences, 2015National Acad Sciences
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 …
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.
National Acad Sciences