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

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.