Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics
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CitationKuo, Szu-Yu, Adam B. Castoreno, Leslie N. Aldrich, Kara G. Lassen, Gautam Goel, Vlado Dančík, Petric Kuballa, et al. 2015. “Small-Molecule Enhancers of Autophagy Modulate Cellular Disease Phenotypes Suggested by Human Genetics.” Proceedings of the National Academy of Sciences 112 (31): E4281–87. https://doi.org/10.1073/pnas.1512289112.
AbstractStudies 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.
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