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

Abstract

Sirtuin 2 (SIRT2) is an NAD⁺-dependent lysine deacylase that is a member of the sirtuin enzyme family and plays essential roles in cytoskeletal regulation, chromatin remodeling, metabolic control, inflammation, neurodegeneration, and cancer progression. Its diverse biological functions have positioned SIRT2 as a compelling but challenging therapeutic target. This review provides an integrated overview of recent advances in SIRT2 structural biology, emphasizing the catalytic core, substrate-binding channel, and the inducible selectivity pocket that enables isoform discrimination. We summarize the medicinal chemistry landscape of classical SIRT2 inhibitors, highlighting major scaffolds and determinants of potency and selectivity. Emerging strategies based on targeted protein degradation-including SirReal-derived PROTACs, hydrophobic-tag degraders, and non-CRBN E3 ligase systems-are discussed in comparison with traditional occupancy-driven inhibition, underscoring the advantages of event-driven degradation for eliminating both catalytic and non-catalytic SIRT2 functions. Drug repurposing efforts and computational screening approaches further expand the repertoire of potential SIRT2 modulators. Finally, we outline current challenges and future directions, including the need for improved selectivity, better pharmacokinetic profiles, deeper mechanistic understanding, and development of chemical probes for underexplored sirtuin isoforms. Together, these advances highlight the rapidly evolving landscape of SIRT2-targeted therapeutics and their emerging potential in oncology, neurodegeneration, and metabolic disease.