Year: 2025
Type: article
Abstract: 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 FM69 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.
Source: Molecules
Authors: Matthias Frei, Thomas Wein, Franz Bracher
Institution: Ludwig-Maximilians-Universität München
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,258
Funder: Deutsche Forschungsgemeinschaft
OpenAlex ID: W4409407146