Advances in SIRT2-Targeted Therapeutics: Structural Insights, Chemical Strategies, and Degrader Technologies

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Sirtuin 2 (SIRT2) is an NAD⁺-dependent lysine deacylase involved in critical cellular processes like metabolism, inflammation, and neurodegeneration.
• Its multifaceted roles make SIRT2 a significant, yet challenging, therapeutic target for various diseases, including cancer and neurodegenerative disorders.

Purpose of the Study:

• To provide a comprehensive review of recent advancements in SIRT2 structural biology and medicinal chemistry.
• To compare traditional inhibition strategies with emerging targeted protein degradation approaches for modulating SIRT2 activity.
• To highlight current challenges and future directions in the development of SIRT2-targeted therapeutics.

Main Methods:

• Review of recent literature on SIRT2 structural biology, focusing on its catalytic core, substrate-binding channel, and selectivity pocket.
• Summary of medicinal chemistry efforts, including major scaffolds and selectivity determinants of classical SIRT2 inhibitors.
• Discussion of emerging strategies like Proteolysis-Targeting Chimeras (PROTACs) and other targeted protein degradation systems.

Main Results:

• Detailed insights into SIRT2 structural features influencing substrate binding and isoform discrimination.
• Overview of established SIRT2 inhibitor scaffolds and their structure-activity relationships.
• Comparison of occupancy-driven inhibition versus event-driven degradation, emphasizing the benefits of the latter for eliminating SIRT2 functions.

Conclusions:

• Targeted protein degradation represents a powerful alternative to traditional inhibition for modulating SIRT2.
• Drug repurposing and computational screening expand the toolkit for identifying novel SIRT2 modulators.
• Future research should focus on enhancing selectivity, improving pharmacokinetics, and developing probes for less-studied sirtuin isoforms.