Journal article
A homogeneous time-resolved fluorescence screen to identify SIRT2 deacetylase and defatty-acylase inhibitors
PloS one, v 19(6), e0305000
01 Jan 2024
Featured in Collection : UN Sustainable Development Goals @ Drexel
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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Details
- Title
- A homogeneous time-resolved fluorescence screen to identify SIRT2 deacetylase and defatty-acylase inhibitors
- Creators
- Jie Yang - Rowan UniversityJoel Cassel - Protein ExpressBrian C Boyle - Rowan UniversityDaniel Oppong - Drexel UniversityYoung-Hoon AhnBrian P Weiser - Rowan University
- Publication Details
- PloS one, v 19(6), e0305000
- Publisher
- PLOS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:001255170400037
- Scopus ID
- 2-s2.0-85196984583
- Other Identifier
- 991021893681504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology