Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in S. cerevisiae
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 as...
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| 语言: | en_US |
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American Chemical Society (ACS)
2015
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| 在线阅读: | http://hdl.handle.net/1721.1/96732 https://orcid.org/0000-0002-1446-7256 |
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| author | Liu, Qingsong Ren, Tao Fresques, Tara Oppliger, Wolfgang Niles, Brad J. Hur, Wooyoung Hall, Michael N. Powers, Ted Gray, Nathanael S. Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Liu, Qingsong Ren, Tao Fresques, Tara Oppliger, Wolfgang Niles, Brad J. Hur, Wooyoung Hall, Michael N. Powers, Ted Gray, Nathanael S. Sabatini, David |
| author_sort | Liu, Qingsong |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T07:58:34Z |
| format | Article |
| id | mit-1721.1/96732 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T07:58:34Z |
| publishDate | 2015 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/967322022-09-30T01:24:46Z Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in S. cerevisiae 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 Hall, Michael N. Powers, Ted Gray, Nathanael S. Sabatini, David Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Sabatini, David M. 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. 2015-04-23T14:56:38Z 2015-04-23T14:56:38Z 2012-04 2012-02 Article http://purl.org/eprint/type/JournalArticle 1554-8929 1554-8937 http://hdl.handle.net/1721.1/96732 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. https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1021/cb300058v ACS Chemical Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Liu, Qingsong Ren, Tao Fresques, Tara Oppliger, Wolfgang Niles, Brad J. Hur, Wooyoung Hall, Michael N. Powers, Ted Gray, Nathanael S. Sabatini, David Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in S. cerevisiae |
| title | Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in S. cerevisiae |
| title_full | Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in S. cerevisiae |
| title_fullStr | Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in S. cerevisiae |
| title_full_unstemmed | Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in S. cerevisiae |
| title_short | Selective ATP-Competitive Inhibitors of TOR Suppress Rapamycin-Insensitive Function of TORC2 in S. cerevisiae |
| title_sort | selective atp competitive inhibitors of tor suppress rapamycin insensitive function of torc2 in s cerevisiae |
| url | http://hdl.handle.net/1721.1/96732 https://orcid.org/0000-0002-1446-7256 |
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