Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in saccharomyces cerevisiae

Qingsong Liu, Tao Ren, Tara Fresques, Wolfgang Oppliger, Brad J. Niles, Wooyoung Hur, David M. Sabatini, Michael N. Hall, Ted Powers, Nathanael S. Gray

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)982-987
Number of pages6
JournalACS Chemical Biology
Volume7
Issue number6
DOIs
StatePublished - Jun 15 2012

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Sirolimus
Yeast
Saccharomyces cerevisiae
Adenosine Triphosphate
Assays
Phosphotransferases
Phosphorylation
Cell proliferation
Transcription
Growth
Energy Metabolism
Libraries
Signal Transduction
Yeasts
Alleles
Binding Sites
Cell Proliferation
TOR complex 2
Substrates
mechanistic target of rapamycin complex 1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in saccharomyces cerevisiae. / Liu, Qingsong; Ren, Tao; Fresques, Tara; Oppliger, Wolfgang; Niles, Brad J.; Hur, Wooyoung; Sabatini, David M.; Hall, Michael N.; Powers, Ted; Gray, Nathanael S.

In: ACS Chemical Biology, Vol. 7, No. 6, 15.06.2012, p. 982-987.

Research output: Contribution to journalArticle

Liu, Q, Ren, T, Fresques, T, Oppliger, W, Niles, BJ, Hur, W, Sabatini, DM, Hall, MN, Powers, T & Gray, NS 2012, 'Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in saccharomyces cerevisiae', ACS Chemical Biology, vol. 7, no. 6, pp. 982-987. https://doi.org/10.1021/cb300058v
Liu, Qingsong ; Ren, Tao ; Fresques, Tara ; Oppliger, Wolfgang ; Niles, Brad J. ; Hur, Wooyoung ; Sabatini, David M. ; Hall, Michael N. ; Powers, Ted ; Gray, Nathanael S. / Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in saccharomyces cerevisiae. In: ACS Chemical Biology. 2012 ; Vol. 7, No. 6. pp. 982-987.
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