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Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics.
Kuo, Szu-Yu; Castoreno, Adam B; Aldrich, Leslie N; Lassen, Kara G; Goel, Gautam; Dancík, Vlado; Kuballa, Petric; Latorre, Isabel; Conway, Kara L; Sarkar, Sovan; Maetzel, Dorothea; Jaenisch, Rudolf; Clemons, Paul A; Schreiber, Stuart L; Shamji, Alykhan F; Xavier, Ramnik J.
Afiliación
  • Kuo SY; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138;
  • Castoreno AB; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
  • Aldrich LN; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138;
  • Lassen KG; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142;
  • Goel G; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114;
  • Dancík V; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
  • Kuballa P; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114;
  • Latorre I; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
  • Conway KL; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142;
  • Sarkar S; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142; Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
  • Maetzel D; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142;
  • Jaenisch R; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142; Skolkovo Institute of Science and Technology (Skoltech), Skolkovo 143025, Moscow Region, Russia;
  • Clemons PA; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142;
  • Schreiber SL; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; Howard Hughes Medical Institute, Cambridge, MA 02142 stuart_schreiber@harvard.edu ashamji@broadinstitute.org xavier@molbio.mgh.harvard.
  • Shamji AF; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142; stuart_schreiber@harvard.edu ashamji@broadinstitute.org xavier@molbio.mgh.harvard.edu.
  • Xavier RJ; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142; Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114; stuart_schreiber
Proc Natl Acad Sci U S A ; 112(31): E4281-7, 2015 Aug 04.
Article en En | MEDLINE | ID: mdl-26195741
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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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Autofagia / Enfermedad de Niemann-Pick Tipo C / Bibliotecas de Moléculas Pequeñas / Genética Médica Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2015 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Autofagia / Enfermedad de Niemann-Pick Tipo C / Bibliotecas de Moléculas Pequeñas / Genética Médica Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2015 Tipo del documento: Article