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


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.

SUBMITTER: Kuo SY 

PROVIDER: S-EPMC4534235 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Kuo Szu-Yu SY   Castoreno Adam B AB   Aldrich Leslie N LN   Lassen Kara G KG   Goel Gautam G   Dančík Vlado V   Kuballa Petric P   Latorre Isabel I   Conway Kara L KL   Sarkar Sovan S   Maetzel Dorothea D   Jaenisch Rudolf R   Clemons Paul A PA   Schreiber Stuart L SL   Shamji Alykhan F AF   Xavier Ramnik J RJ  

Proceedings of the National Academy of Sciences of the United States of America 20150720 31


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  ...[more]

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