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

doi:10.1073/pnas.1512289112

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

Cancer and Genomic Sciences

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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 language	English
Pages (from-to)	E4281-E4287
Journal	National Academy of Sciences. Proceedings
Volume	112
Issue number	31
DOIs	https://doi.org/10.1073/pnas.1512289112
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1512289112

E4281.full
Eligibility for repository: Checked on 13/1/2016
Final published version, 1.2 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

Kuo, S-Y., Castoreno, A. B., Aldrich, L. N., Lassen, K. G., Goel, G., Dančík, V., Kuballa, P., Latorre, I., Conway, K. L., Sarkar, S., Maetzel, D., Jaenisch, R., Clemons, P. A., Schreiber, S. L., Shamji, A. F., & Xavier, R. J. (2015). Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics. National Academy of Sciences. Proceedings, 112(31), E4281-E4287. https://doi.org/10.1073/pnas.1512289112

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title = "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.",

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author = "Szu-Yu Kuo and Castoreno, {Adam B} and Aldrich, {Leslie N} and Lassen, {Kara G} and Gautam Goel and Vlado Dan{\v c}{\'i}k and Petric Kuballa and Isabel Latorre and Conway, {Kara L} and Sovan Sarkar and Dorothea Maetzel and Rudolf Jaenisch and Clemons, {Paul A} and Schreiber, {Stuart L} and Shamji, {Alykhan F} and Xavier, {Ramnik J}",

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Kuo, S-Y, Castoreno, AB, Aldrich, LN, Lassen, KG, Goel, G, Dančík, V, Kuballa, P, Latorre, I, Conway, KL, Sarkar, S, Maetzel, D, Jaenisch, R, Clemons, PA, Schreiber, SL, Shamji, AF & Xavier, RJ 2015, 'Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics', National Academy of Sciences. Proceedings, vol. 112, no. 31, pp. E4281-E4287. https://doi.org/10.1073/pnas.1512289112

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AU - Kuo, Szu-Yu

AU - Castoreno, Adam B

AU - Aldrich, Leslie N

AU - Lassen, Kara G

AU - Goel, Gautam

AU - Dančík, Vlado

AU - Kuballa, Petric

AU - Latorre, Isabel

AU - Conway, Kara L

AU - Sarkar, Sovan

AU - Maetzel, Dorothea

AU - Jaenisch, Rudolf

AU - Clemons, Paul A

AU - Schreiber, Stuart L

AU - Shamji, Alykhan F

AU - Xavier, Ramnik J

PY - 2015/8/4

Y1 - 2015/8/4

N2 - 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.

AB - 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.

KW - Autophagy

KW - Bacteria

KW - Carrier Proteins

KW - Cell Aggregation

KW - Genetics, Medical

KW - Green Fluorescent Proteins

KW - HeLa Cells

KW - High-Throughput Screening Assays

KW - Humans

KW - Induced Pluripotent Stem Cells

KW - Interleukin-1beta

KW - Membrane Glycoproteins

KW - Models, Biological

KW - Neurons

KW - Niemann-Pick Disease, Type C

KW - Peptides

KW - Phenotype

KW - Small Molecule Libraries

U2 - 10.1073/pnas.1512289112

DO - 10.1073/pnas.1512289112

M3 - Article

C2 - 26195741

SN - 1091-6490

VL - 112

SP - E4281-E4287

JO - National Academy of Sciences. Proceedings

JF - National Academy of Sciences. Proceedings

IS - 31

ER -

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

Abstract

Keywords

UN SDGs

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