Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in S. cerevisiae
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Sabatini_Selective ATP.pdf
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Author(s)
Liu, Qingsong
Ren, Tao
Fresques, Tara
Oppliger, Wolfgang
Niles, Brad J.
Hur, Wooyoung
Hall, Michael N.
Powers, Ted
Gray, Nathanael S.
Sabatini, David
Alternative Title
Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in Saccharomyces cerevisiae
Date Issued
April 2012
Journal
ACS Chemical Biology
Publisher
American Chemical Society (ACS)
Citation
Liu, Qingsong, Tao Ren, Tara Fresques, Wolfgang Oppliger, Brad J. Niles, Wooyoung Hur, David M. Sabatini, Michael N. Hall, Ted Powers, and Nathanael S. Gray. “Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in Saccharomyces Cerevisiae.” ACS Chemical Biology 7, no. 6 (June 15, 2012): 982–987.
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Author's final manuscript
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[subscript 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1021/cb300058v
