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  3. A homogeneous time-resolved fluorescence screen to identify SIRT2 deacetylase and defatty-acylase inhibitors

A homogeneous time-resolved fluorescence screen to identify SIRT2 deacetylase and defatty-acylase inhibitors

  • PLoS One. 2024 Jun 24;19(6):e0305000. doi: 10.1371/journal.pone.0305000.
Jie Yang 1 2,  Joel Cassel 3,  Brian C Boyle 1 2 4,  Daniel Oppong 5,  Young-Hoon Ahn 5,  Brian P Weiser 1 2
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Rowan-Virtua School of Translational Biomedical Engineering & Sciences, Rowan University, Stratford, New Jersey, United States of America.
  • 2 Department of Molecular Biology, Rowan-Virtua School of Osteopathic Medicine, Rowan University, Stratford, New Jersey, United States of America.
  • 3 Molecular Screening & Protein Expression Facility, Wistar Institute, Philadelphia, Pennsylvania, United States of America.
  • 4 Department of Biomedical Engineering, Rowan-Virtua School of Translational Biomedical Engineering & Sciences, Rowan University, Glassboro, New Jersey, United States of America.
  • 5 Department of Chemistry, Drexel University, Philadelphia, Pennsylvania, United States of America.
PMID: 38913635 DOI: 10.1371/journal.pone.0305000
Abstract

Human sirtuin-2 (SIRT2) has emerged as an attractive drug target for a variety of diseases. The Enzyme is a deacylase that can remove chemically different acyl modifications from protein lysine residues. Here, we developed a high-throughput screen based on a homogeneous time-resolved fluorescence (HTRF) binding assay to identify inhibitors of SIRT2's demyristoylase activity, which is uncommon among many ligands that only affect its deacetylase activity. From a test screen of 9600 compounds, we identified a small molecule that inhibited SIRT2's deacetylase activity (IC50 = 7 μM) as well as its demyristoylase activity (IC50 = 37 μM). The inhibitor was composed of two small fragments that independently inhibited SIRT2: a halogenated phenol fragment inhibited its deacetylase activity, and a tricyclic thiazolobenzimidazole fragment inhibited its demyristoylase activity. The high-throughput screen also detected multiple deacetylase-specific SIRT2 inhibitors.

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