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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Targeting sirtuins (SIRTs) for cancer therapy remains controversial due to a lack of specific inhibitors.
• Existing sirtuin inhibitors often lack potency and specificity, limiting their therapeutic application.

Purpose of the Study:

• To develop a potent and specific inhibitor for sirtuin 2 (SIRT2).
• To investigate the anticancer effects and underlying mechanisms of the novel SIRT2 inhibitor.
• To evaluate the therapeutic potential of SIRT2-selective inhibitors in preclinical cancer models.

Main Methods:

• Development of a thiomyristoyl lysine compound (TM) as a SIRT2 inhibitor.
• Assessment of TM's anticancer activity in various human cancer cell lines.
• Evaluation of TM in mouse models of breast cancer.
• Mechanistic studies involving c-Myc ubiquitination and degradation assays.

Main Results:

• TM demonstrated potent and specific inhibition of SIRT2.
• TM exhibited broad anticancer effects across multiple cancer cell types and in breast cancer mouse models.
• SIRT2 inhibition by TM led to increased c-Myc ubiquitination and subsequent degradation.
• The anticancer efficacy of TM correlated with reduced c-Myc levels.
• TM showed minimal toxicity in non-cancerous cells and tumor-free mice.

Conclusions:

• SIRT2-selective inhibitors, exemplified by TM, are promising anticancer agents.
• Targeting SIRT2 exploits cancer cell dependency, offering a therapeutic window.
• SIRT2 inhibition represents a potential therapeutic strategy for cancers driven by c-Myc.