title: A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity.
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.
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Jing
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Yashira L
authors.initials: YL
authors.lastname: Negrón Abril
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Stupinski
authors.affiliation: Division of Hematology & Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, C610C, New York, NY 10065-4896, USA.
authors.forename: Keren
authors.initials: K
authors.lastname: Weiser
authors.affiliation: Division of Hematology & Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, C610C, New York, NY 10065-4896, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Carbonaro
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Ying-Ling
authors.initials: YL
authors.lastname: Chiang
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Southard
authors.affiliation: Division of Hematology & Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, C610C, New York, NY 10065-4896, USA.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Giannakakou
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weiss
authors.affiliation: 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: hl379@cornell.edu.
authors.forename: Hening
authors.initials: H
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D056565:Sirtuin 2; D008239:Lysine