MDL 800 is a selective allosteric activator of Sirtuin 6 (SIRT6) with EC50 value of 10.3μM[1]. SIRT6, widely expressed in almost all mammalian organs, is involved in many biological processes, such as DNA repair, glucose/lipid metabolism, inflammation, aging and tumor suppression[2 - 4].
In vitro, treatment of NSCLC cells with MDL 800(10–50μM, 48h) increased SIRT6 deacetylase activity, induced deacetylation of histone H3 and inhibited cell proliferation in a dose-dependent manner[5]. MDL 800 (0.1-5µM) inhibits TNF-α release induced by oxygen and glucose deprivation (OGD) in primary mouse microglia[6].
In vivo,intraperitoneal injection of MDL 800(50, 100, and 150mg/kg/day) for 2 weeks suppressed the growth of Bel7405 xenografts and decreased tumor weight and size in a dose-dependent manner in mouse model with Bel7405 xenograft[1]. In mice with a full thickness cutaneous wound model, itraperitoneal injection of MDL 800(5, 25mg/kg/day) for 7 days attenuated the release of inflammatory mediators and improved collagen deposition and neovascularization of wounds. Furthermore, MDL 800 significantly downregulated expression levels of TNF-α and IL-6 in the dorsal skin tissue of mice[7].
References:
[1] Huang, Z., Zhao, J., Deng, W., Chen, Y., Shang, J., Song, K., Zhang, L., Wang, C., Lu, S., Yang, X., He, B., Min, J., Hu, H., Tan, M., Xu, J., Zhang, Q., Zhong, J., Sun, X., Mao, Z., Lin, H., … Zhang, J. (2018). Identification of a cellularly active SIRT6 allosteric activator. Nature chemical biology, 14(12), 1118–1126.
[2] Kugel, S., & Mostoslavsky, R. (2014). Chromatin and beyond: the multitasking roles for SIRT6. Trends in biochemical sciences, 39(2), 72–81.
[3] Tasselli, L., Zheng, W., & Chua, K. F. (2017). SIRT6: Novel Mechanisms and Links to Aging and Disease. Trends in endocrinology and metabolism: TEM, 28(3), 168–185.
[4] Van Meter M, Gorbunova V, Seluanov A. SIRT6: a promising target for cancer prevention and therapy. Advances in Experimental Medicine and Biology, 2014, 818: 181-196.
[5] Shang, J. L., Ning, S. B., Chen, Y. Y., Chen, T. X., & Zhang, J. (2021). MDL-800, an allosteric activator of SIRT6, suppresses proliferation and enhances EGFR-TKIs therapy in non-small cell lung cancer. Acta pharmacologica Sinica, 42(1), 120–131.
[6] He, T., Shang, J., Gao, C., Guan, X., Chen, Y., Zhu, L., Zhang, L., Zhang, C., Zhang, J., & Pang, T. (2021). A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis. Acta pharmaceutica Sinica. B, 11(3), 708–726.
[7] Jiang, X., Yao, Z., Wang, K., Lou, L., Xue, K., Chen, J., Zhang, G., Zhang, Y., Du, J., Lin, C., & Xiao, J. (2022). MDL-800, the SIRT6 Activator, Suppresses Inflammation via the NF-κB Pathway and Promotes Angiogenesis to Accelerate Cutaneous Wound Healing in Mice. Oxidative medicine and cellular longevity, 2022, 1619651.
MDL 800是一种Sirtuin 6（SIRT6）的选择性变构激活剂，EC50值为10.3μM[1]。SIRT6在哺乳动物几乎所有器官中广泛表达，参与多种生物过程，如DNA修复、糖脂代谢、炎症、衰老和肿瘤抑制等[2 - 4]。
在体外实验中，用MDL 800（10–50μM，48h）处理非小细胞肺癌（NSCLC）细胞，可增强SIRT6去乙酰化酶活性，并以剂量依赖性方式诱导组蛋白H3去乙酰化且抑制细胞增殖[5]。MDL 800（0.1-5µM）可抑制因缺氧和葡萄糖剥夺（OGD）诱导的小鼠原代小胶质细胞中TNF-α的释放[6]。
在体内实验中，在Bel7405异种移植小鼠模型中，腹腔注射MDL 800（50、100和150mg/kg/day）2周可抑制肿瘤生长，并以剂量依赖方式减少肿瘤重量和体积[1]。在小鼠全层皮肤伤口模型中，持续腹腔注射MDL 800（5、25mg/kg/day）7天可减轻炎症介质的释放，改善伤口的胶原沉积和新生血管形成。此外，MDL 800显著下调小鼠背侧皮肤组织中TNF-α和IL-6的表达水平[7]。