Screening of SIRT6 inhibitors and activators: A novel activator has an impact on breast cancer cells

• Published in: Biomedicine & pharmacotherapy Vol. 138; p. 111452
• Main Authors: Tenhunen, Jonna, Kučera, Tomáš, Huovinen, Marjo, Küblbeck, Jenni, Bisenieks, Egils, Vigante, Brigita, Ogle, Zaiga, Duburs, Gunars, Doležal, Martin, Moaddel, Ruin, Lahtela-Kakkonen, Maija, Rahnasto-Rilla, Minna
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.06.2021; Elsevier
• Subjects: Activator; Breast cancer; Inhibitor; Sirtuin 6; Virtual screening; Virtual screening; Breast cancer; Inhibitor; Activator; Sirtuin 6
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.111452

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. [Display omitted] •A virtual screening provided several SIRT6 modulators.•4H-chromen provided 40-fold activation whereas 1,4-dihydropyridines inhibited SIRT6.•4H-chromen showed anti-cancer activities on various breast cancer cells.