SIRT6 inhibitors with salicylate-like structure show immunosuppressive and chemosensitizing effects

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• SIRT6, a NAD+-dependent deacetylase, is a promising cancer drug target.
• Inhibiting SIRT6 can sensitize cancer cells to chemo-radiotherapy and promote differentiation.

Purpose of the Study:

• To identify novel SIRT6 inhibitors with improved potency and specificity.
• To evaluate the biological activity and drug-like properties of these new inhibitors.

Main Methods:

• In silico compound screening followed by chemical synthesis.
• Cell-based assays measuring histone acetylation, glucose uptake, TNF-α production, and T lymphocyte proliferation.
• In vitro studies on pancreatic cancer cell sensitization to gemcitabine.
• Pharmacokinetic and compound fingerprinting analyses.

Main Results:

• Novel salicylate-based SIRT6 inhibitors were identified with enhanced potency and specificity.
• In vitro studies confirmed increased histone 3 lysine 9 acetylation, glucose uptake, and blocked TNF-α production and T lymphocyte proliferation.
• The inhibitors effectively sensitized pancreatic cancer cells to gemcitabine.
• One inhibitor demonstrated favorable drug-like properties for potential in vivo studies.

Conclusions:

• New salicylate-like SIRT6 inhibitors are active in cellular models.
• These compounds show potential for treating cancer and immune-mediated disorders.
• Further in vivo studies are warranted to explore therapeutic applications.