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Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in Saccharomyces cerevisiae

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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Chem. Biol. 2012, 7, 6, 982-987
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    Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in Saccharomyces cerevisiae
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    † Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, United States
    ‡ Department of Biology Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, United States
    § Harvard Medical School, Boston, Massachusetts 02115, United States
    ∥ Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, California 95616, United States
    ⊥ Biozentrum, University of Basel, CH-4056 Basel, Switzerland
    # Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, United States
    Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    ○ Koch Center for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    *E-mail: [email protected]
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2012, 7, 6, 982–987
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    https://doi.org/10.1021/cb300058v
    Published April 11, 2012
    Copyright © 2012 American Chemical Society
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    Abstract

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    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 (IC50 <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.

    Copyright © 2012 American Chemical Society

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    Supporting Information

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    Supplemental experimental procedures, Tables S1–S3, Figures S1–S3, and supplemental references. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cited By

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    This article is cited by 11 publications.

    1. Ruiqiang Ye, Meiyue Wang, Hao Du, Shweta Chhajed, Jin Koh, Kun-hsiang Liu, Jinwoo Shin, Yue Wu, Lin Shi, Lin Xu, Sixue Chen, Yijing Zhang, Jen Sheen. Glucose-driven TOR–FIE–PRC2 signalling controls plant development. Nature 2022, 609 (7929) , 986-993. https://doi.org/10.1038/s41586-022-05171-5
    2. Marc S. Rendell. Current and emerging gluconeogenesis inhibitors for the treatment of Type 2 diabetes. Expert Opinion on Pharmacotherapy 2021, 22 (16) , 2167-2179. https://doi.org/10.1080/14656566.2021.1958779
    3. Yeonji Chang, Gyubum Lim, Won-Ki Huh. Analysis of the TORC1 interactome reveals a spatially distinct function of TORC1 in mRNP complexes. Journal of Cell Biology 2021, 220 (4) https://doi.org/10.1083/jcb.201912060
    4. Marie-Hélène Montané, Benoît Menand. TOR inhibitors: from mammalian outcomes to pharmacogenetics in plants and algae. Journal of Experimental Botany 2019, 70 (8) , 2297-2312. https://doi.org/10.1093/jxb/erz053
    5. Melissa N. Locke, Jeremy Thorner. Rab5 GTPases are required for optimal TORC2 function. Journal of Cell Biology 2019, 218 (3) , 961-976. https://doi.org/10.1083/jcb.201807154
    6. Pavan Kumar, Ankita Awasthi, Vikrant Nain, Biju Issac, Rekha Puria. Novel insights into TOR signalling in Saccharomyces cerevisiae through Torin2. Gene 2018, 669 , 15-27. https://doi.org/10.1016/j.gene.2018.05.081
    7. Mitchell B. Lee, Daniel T. Carr, Michael G. Kiflezghi, Yan Ting Zhao, Deborah B. Kim, Socheata Thon, Margarete D. Moore, Mary Ann K. Li, Matt Kaeberlein. A system to identify inhibitors of mTOR signaling using high-resolution growth analysis in Saccharomyces cerevisiae. GeroScience 2017, 39 (4) , 419-428. https://doi.org/10.1007/s11357-017-9988-4
    8. Tzung-Ju Wu, Xiaowen Wang, Yanjie Zhang, Linghua Meng, John E. Kerrigan, Stephen K. Burley, X.F. Steven Zheng. Identification of a Non-Gatekeeper Hot Spot for Drug-Resistant Mutations in mTOR Kinase. Cell Reports 2015, 11 (3) , 446-459. https://doi.org/10.1016/j.celrep.2015.03.040
    9. Gabriela Caraveo, Pavan K. Auluck, Luke Whitesell, Chee Yeun Chung, Valeriya Baru, Eugene V. Mosharov, Xiaohui Yan, Manu Ben-Johny, Martin Soste, Paola Picotti, Hanna Kim, Kim A. Caldwell, Guy A. Caldwell, David Sulzer, David T. Yue, Susan Lindquist. Calcineurin determines toxic versus beneficial responses to α-synuclein. Proceedings of the National Academy of Sciences 2014, 111 (34) https://doi.org/10.1073/pnas.1413201111
    10. Joseph I. Kliegman, Dorothea Fiedler, Colm J. Ryan, Yi-Fan Xu, Xiao-yang Su, David Thomas, Max C. Caccese, Ada Cheng, Michael Shales, Joshua D. Rabinowitz, Nevan J. Krogan, Kevan M. Shokat. Chemical Genetics of Rapamycin-Insensitive TORC2 in S. cerevisiae. Cell Reports 2013, 5 (6) , 1725-1736. https://doi.org/10.1016/j.celrep.2013.11.040
    11. Marie-Hélène Montané, Benoît Menand. ATP-competitive mTOR kinase inhibitors delay plant growth by triggering early differentiation of meristematic cells but no developmental patterning change. Journal of Experimental Botany 2013, 64 (14) , 4361-4374. https://doi.org/10.1093/jxb/ert242
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2012, 7, 6, 982–987
    Click to copy citationCitation copied!
    https://doi.org/10.1021/cb300058v
    Published April 11, 2012
    Copyright © 2012 American Chemical Society
    Request reuse permissions

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