Unlocking the Therapeutic Potential of Heterocyclic Molecules as SIRT2 Inhibitors: Advancing Therapeutic Frontiers

Abstract Silent information regulators (sirtuins) are nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that participate in numerous physiological processes in humans. Among the seven human sirtuins, sirtuin 2 (SIRT2) is one of the most extensively characterized isoforms, playing a pivotal role in cellular aging, energy metabolism, and genomic stability. This review summarizes recent advances in the development of small-molecule SIRT2 inhibitors, highlighting their half-maximal inhibitory concentrations (IC50 values). A concise structure–activity relationship (SAR) analysis explores the critical pharmacophores and chemical probes responsible for SIRT2 inhibition, providing insights for lead optimization and the design of novel therapeutics. This comprehensive overview is expected to facilitate the rational design of next-generation, highly potent, and selective SIRT2 inhibitors.