title: Discovery of a Small-Molecule Probe for V-ATPase Function.
abstract: Lysosomes perform a critical cellular function as a site of degradation for diverse cargoes including proteins, organelles, and pathogens delivered through distinct pathways, and defects in lysosomal function have been implicated in a number of diseases. Recent studies have elucidated roles for the lysosome in the regulation of protein synthesis, metabolism, membrane integrity, and other processes involved in homeostasis. Complex small-molecule natural products have greatly contributed to the investigation of lysosomal function in cellular physiology. Here we report the discovery of a novel, small-molecule modulator of lysosomal acidification derived from diversity-oriented synthesis through high-content screening.
authors: †Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States.|‡Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Leslie N
authors: LN
authors: Aldrich
authors: ‡Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.|§Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, Massachusetts 02138, United States.
authors: Szu-Yu
authors: SY
authors: Kuo
authors: ‡Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Adam B
authors: AB
authors: Castoreno
authors: ∥Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States.|⊥Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, United States.|#Program in Medical and Population Genetics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Gautam
authors: G
authors: Goel
authors: ∥Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States.|⊥Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, United States.|#Program in Medical and Population Genetics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Petric
authors: P
authors: Kuballa
authors: ‡Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Matthew G
authors: MG
authors: Rees
authors: ‡Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Brinton A
authors: BA
authors: Seashore-Ludlow
authors: ‡Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Jaime H
authors: JH
authors: Cheah
authors: ‡Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Isabel J
authors: IJ
authors: Latorre
authors: †Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States.|‡Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.|∇Howard Hughes Medical Institute, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Stuart L
authors: SL
authors: Schreiber
authors: ‡Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Alykhan F
authors: AF
authors: Shamji
authors: ∥Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States.|⊥Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, United States.|#Program in Medical and Population Genetics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors: Ramnik J
authors: RJ
authors: Xavier
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; D054852:Small Molecule Libraries; C040929:bafilomycin A1; D025262:Vacuolar Proton-Translocating ATPases