School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Faculty of Pharmacy in Hradec Králové, Charles University, Prague, Czech Republic.
Biomed Pharmacother. 2021 Jun;138:111452. doi: 10.1016/j.biopha.2021.111452. Epub 2021 Mar 5.
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.
Sirtuin 6 (SIRT6)，是 sirtuin 家族（SIRT1-7）的一员，调节多种与衰老、代谢和癌症相关的细胞过程。SIRT6 的失调在不同的乳腺癌亚型中广泛观察到；然而，SIRT6 在癌症发展中的作用和功能在很大程度上仍未被探索。本研究的目的是鉴定靶向 SIRT6 的新型化合物，这可能为开发乳腺癌的抗癌治疗提供新方法。利用虚拟筛选发现潜在的靶向 SIRT6 的化合物，进行体外筛选。此外，还合成了新型 1,4-二氢吡啶衍生物，并进一步进行筛选。用 HPLC 法测定化合物对 SIRT6 去乙酰化活性的影响。对一组乳腺癌细胞进行了抗癌活性筛选。一组 1,4-二氢吡啶衍生物被鉴定为 SIRT6 抑制剂。发现了一种 SIRT6 激活化合物，（2,4-二羟基-苯基）-2-氧代乙基 2-（3-甲基-4-氧代-2-苯基-4H-色烯-8-基）乙酸酯（后称为 4H-色烯），它提供了 30-40 倍的最大激活。4H-色烯被提议与槲皮素类似结合，并占据先前报道的 SIRT6 激活剂的位置。4H-色烯在各种乳腺癌细胞中进行了研究，它在所有细胞中均降低了细胞增殖，并使三阴性细胞的细胞周期停滞。总的来说，本研究描述了一种高效的 SIRT6 激活剂和新型抑制剂，代表了研究 SIRT6 功能机制的新工具。
