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Screening of SIRT6 inhibitors and activators: A novel activator has an impact on breast cancer cells
J. Tenhunen, T. Kučera, M. Huovinen, J. Küblbeck, E. Bisenieks, B. Vigante, Z. Ogle, G. Duburs, M. Doležal, R. Moaddel, M. Lahtela-Kakkonen, M. Rahnasto-Rilla
Language English Country France
Document type Journal Article
- MeSH
- Early Detection of Cancer methods MeSH
- Humans MeSH
- Breast Neoplasms drug therapy metabolism MeSH
- Antineoplastic Agents chemistry pharmacology therapeutic use MeSH
- Drug Screening Assays, Antitumor methods MeSH
- Protein Structure, Secondary MeSH
- Molecular Docking Simulation methods MeSH
- Sirtuins antagonists & inhibitors chemistry metabolism MeSH
- Protein Structure, Tertiary MeSH
- Cell Survival drug effects physiology MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Sirtuin 6 (SIRT6), a member of sirtuin family (SIRT1-7), regulates a variety of cellular processes involved in aging, metabolism, and cancer. Dysregulation of SIRT6 is widely observed in different breast cancer subtypes; however, the role and function of SIRT6 in cancer development remain largely unexplored. The aim of this study was to identify novel compounds targeting SIRT6 which may provide a new approach in development of anti-cancer therapy for breast cancer. Virtual screening was utilized to discover potential compounds targeting SIRT6 for in vitro screening. In addition, novel 1,4-dihydropyridine derivatives were synthetized and further subjected for the screening. The impact of the compounds on the deacetylation activity of SIRT6 was determined with HPLC method. The anti-cancer activities were screened for a panel of breast cancer cells. A set of 1,4-dihydropyridine derivatives was identified as SIRT6 inhibitors. A SIRT6 activating compound, (2,4-dihydroxy-phenyl)-2-oxoethyl 2-(3-methyl-4-oxo-2-phenyl-4H-chromen-8-yl)acetate (later called as 4H-chromen), was discovered and it provided 30-40-fold maximal activation. 4H-chromen was proposed to bind similarly to quercetin and place to previously reported SIRT6 activator sites. 4H-chromen was investigated in various breast cancer cells, and it decreased cell proliferation in all cells as well as arrested cell cycle in triple negative cells. Overall, this study describes a highly potent SIRT6 activator and new inhibitors that represent a novel tool to study the mechanism of SIRT6 function.
Faculty of Pharmacy in Hradec Králové Charles University Prague Czech Republic
Latvian Institute of Organic Synthesis Riga Latvia
School of Pharmacy University of Eastern Finland Kuopio Finland
References provided by Crossref.org
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