Lead-Structure-Based Rigidization Approach to Optimize SirReal-Type Sirt2 Inhibitors

Sirtuins are involved in cellular processes in multiple ways. Therefore, the development of potent and selective Sirt2 inhibitors provides an important contribution to understanding physiological and pathophysiological mechanisms, particularly for the research and treatment of cancer and neurodegenerative diseases. Based on established SirReal-type lead inhibitors, further selective Sirt2 inhibitors were synthesized in a docking-guided rigidization approach, and the knowledge regarding requirements and properties of the Sirt2-binding pocket was expanded by means of a comprehensive SAR study. Naphthalene derivative <b>FM69</b> emerged from the screening as the most potent rigidized inhibitor, which, with an IC₅₀ value of 0.15 µM against Sirt2, represents a promising foundation for the further development of novel potent and selective Sirt2 inhibitors based on the presented rigidization strategy.