Direct Comparison of SIRT2 Inhibitors: Potency, Specificity, Activity-Dependent Inhibition, and On-Target Anticancer Activities
| Autor: | Pornpun Aramsangtienchai, Ji Cao, Ian R. Price, Hening Lin, Sushabhan Sadhukhan, Hui Jing, Jun Young Hong, Xiaoyu Zhang, Nicole A Spiegelman, Miao Wang, Min Yang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Future studies Cell Survival Antineoplastic Agents Pharmacology SIRT2 Biochemistry Article 03 medical and health sciences Structure-Activity Relationship Sirtuin 2 Drug Discovery medicine Potency Humans General Pharmacology Toxicology and Pharmaceutics Cytotoxicity Cell Proliferation biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Cancer medicine.disease HCT116 Cells In vitro Histone Deacetylase Inhibitors 030104 developmental biology Sirtuin Toxicity biology.protein Molecular Medicine Drug Screening Assays Antitumor |
| Zdroj: | ChemMedChem. 13(18) |
| ISSN: | 1860-7187 |
| Popis: | Sirtuin inhibitors have attracted much interest due to the involvement of sirtuins in various biological processes. Several SIRT2-selective inhibitors have been developed, and some exhibit anticancer activities. To facilitate the choice of inhibitors in future studies and the development of better inhibitors, we directly compared several reported SIRT2-selective inhibitors: AGK2, SirReal2, Tenovin-6, and TM. In vitro, TM is the most potent and selective inhibitor, and only TM could inhibit the demyristoylation activity of SIRT2. SirReal2, Tenovin-6, and TM all showed cytotoxicity in cancer cell lines, with Tenovin-6 being the most potent, but only TM showed cancer-cell-specific toxicity. All four compounds inhibited the anchorage-independent growth of HCT116 cells, but the effect of TM was most significantly affected by SIRT2 overexpression, suggesting that the anticancer effect of TM depends more on SIRT2 inhibition. These results not only provide useful guidance about choosing the right SIRT2 inhibitor in future studies, but also suggest general practices that should be followed for small-molecule inhibitor development activities. |
| Databáze: | OpenAIRE |
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