A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity

  • Cancer Cell. 2016 Mar 14;29(3):297-310. doi: 10.1016/j.ccell.2016.02.007.
Hui Jing  1 ,  Jing Hu  1 ,  Bin He  1 ,  Yashira L Negrón Abril  2 ,  Jack Stupinski  2 ,  Keren Weiser  3 ,  Marisa Carbonaro  3 ,  Ying-Ling Chiang  1 ,  Teresa Southard  2 ,  Paraskevi Giannakakou  3 ,  Robert S Weiss  2 ,  Hening Lin  4
Affiliations
  • 1. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
  • 2. Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
  • 3. Division of Hematology & Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, C610C, New York, NY 10065-4896, USA.
  • 4. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA. Electronic address: [email protected].
PMID: 26977881 DOI: 10.1016/j.ccell.2016.02.007
Abstract

Targeting sirtuins for Cancer treatment has been a topic of debate due to conflicting reports and lack of potent and specific inhibitors. We have developed a thiomyristoyl lysine compound, TM, as a potent SIRT2-specific inhibitor with a broad Anticancer effect in various human Cancer cells and mouse models of breast Cancer. Mechanistically, SIRT2 inhibition promotes c-Myc ubiquitination and degradation. The Anticancer effect of TM correlates with its ability to decrease c-Myc level. TM had limited effects on non-cancerous cells and tumor-free mice, suggesting that Cancer cells have an increased dependency on SIRT2 that can be exploited for therapeutic benefit. Our studies demonstrate that SIRT2-selective inhibitors are promising Anticancer agents and may represent a general strategy to target certain c-Myc-driven cancers.

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