title: Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in Saccharomyces cerevisiae.
abstract: The target of rapamycin (TOR) is a critical regulator of growth, survival, and energy metabolism. The allosteric TORC1 inhibitor rapamycin has been used extensively to elucidate the TOR related signal pathway but is limited by its inability to inhibit TORC2. We used an unbiased cell proliferation assay of a kinase inhibitor library to discover QL-IX-55 as a potent inhibitor of S. cerevisiae growth. The functional target of QL-IX-55 is the ATP-binding site of TOR2 as evidenced by the discovery of resistant alleles of TOR2 through rational design and unbiased selection strategies. QL-IX-55 is capable of potently inhibiting both TOR complex 1 and 2 (TORC1 and TORC2) as demonstrated by biochemical IP kinase assays (IC(50) <50 nM) and cellular assays for inhibition of substrate YPK1 phosphorylation. In contrast to rapamycin, QL-IX-55 is capable of inhibiting TORC2-dependent transcription, which suggests that this compound will be a powerful probe to dissect the Tor2/TORC2-related signaling pathway in yeast.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.forename: Tara
authors.initials: T
authors.lastname: Fresques
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Oppliger
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Niles
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.forename: Ted
authors.initials: T
authors.lastname: Powers
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009181:Mycoses / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; D000935:Antifungal Agents; D018797:Cell Cycle Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D020123:Sirolimus; D014157:Transcription Factors; C081135:TOR2 protein, S cerevisiae; C500749:target of rapamycin protein, S cerevisiae