title: Identification of a small-molecule inhibitor of class Ia PI3Ks with cell-based screening.
abstract: The mammalian target of rapamycin (mTOR) signaling network is central to the regulation of cell growth in response to both growth factors and nutrients. We developed a high-throughput, cell-based assay to identify small-molecule modulators of the mTOR signaling network. One such compound, which we name quinostatin, potently inhibits this network by directly targeting the lipid-kinase activity of the catalytic subunits of class Ia PI3Ks. This study illustrates the power of unbiased, phenotypic screening as a means for illuminating cell circuitry, and resulted in the identification of a chemotype for selective inhibition of the class Ia PI3Ks.
authors.affiliation: Howard Hughes Medical Institute, Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Yang
authors.forename: Alykhan
authors.initials: A
authors.lastname: Shamji
authors.forename: Sirinya
authors.initials: S
authors.lastname: Matchacheep
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D011804:Quinolines; D038601:Ribosomal Protein S6; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C524901:quinostatin; C546842:MTOR protein, human