2‐(Methyl(phenyl)amino)‐N‐(phenyloxyphenyl)acetamide structural motif representing a framework for selective SIRT2 inhibition

• Published in: Drug development research Vol. 85; no. 4; pp. e22224 - n/a
• Main Authors: Kaya, Selen Gozde, Eren, Gokcen, Massarotti, Alberto, Bakar‐Ates, Filiz, Ozkan, Erva, Gozelle, Mahmut, Ozkan, Yesim
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2024
• Subjects: Acetamides - chemistry; Acetamides - pharmacology; Histone deacetylase; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Humans; Lysine; MCF‐7; Metabolic disorders; Molecular Docking Simulation; Neurological diseases; optimization; Pathogenesis; selectivity; sirtuin; Sirtuin 2 - antagonists & inhibitors; Sirtuin 2 - chemistry; Sirtuin 2 - metabolism; Structure-Activity Relationship; Therapeutic targets; α‐tubulin; selectivity; sirtuin; α‐tubulin; optimization; MCF‐7
• ISSN: 0272-4391; 1098-2299; 1098-2299
• DOI: 10.1002/ddr.22224

The mammalian cytoplasmic protein SIRT2, a class III histone deacetylase family member, possesses NAD+‐dependent lysine deacetylase/deacylase activity. Dysregulation of SIRT2 has been implicated in the pathogenesis of several diseases, including neurological and metabolic disorders and cancer; thus, SIRT2 emerges as a potential therapeutic target. Herein, we identified a series of diaryl acetamides (ST61‐ST90) by the structural optimization of our hit STH2, followed by enhanced SIRT2 inhibitory potency and selectivity. Among them, ST72, ST85, and ST88 selectively inhibited SIRT2 with IC50 values of 9.97, 5.74, and 8.92 μM, respectively. Finally, the entire study was accompanied by in silico prediction of binding modes of docked compounds and the stability of SIRT2‐ligand complexes. We hope our findings will provide substantial information for designing selective inhibitors of SIRT2.