MDL-800

MDL-800 is a selective allosteric activator of Sirtuin 6 (SIRT6) with EC50 value of 10.3 μM [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]. 

SIRT6 exhibits different selectivity among histone deacetylase (HDAC) members. When tested with 18 diverse HDAC members, MDL-800 potently activated SIRT6 by increasing SIRT6 deacetylation activity at the concentration of ~10 μM, without showing any activities toward SIRT1, SIRT3, SIRT4 and HDAC1-11 at concentrations up to 50 μM or 100 μM. In human hepatocellular carcinoma (HCC) cells including Bel7405, PLC/PRF/5 and Bel7402 cells, MDL-800 inhibited cell proliferation of with IC50 values of 23.3 μM, 18.6 μM and 24.0 μM, respectively [1]. 

In mouse model with Bel7405 xenograft, intraperitoneal injection of MDL-800 at doses of 50 mg/kg, 100 mg/kg and 150 mg/kg for 2 weeks suppressed the growth of Bel7405 xenografts. MDL-800 decreased tumor weight and size in a dose-dependent manner [1]. 

References:

[1]. Huang Z, Zhao J, Deng W, et al. Identification of a cellularly active SIRT6 allosteric activator. Nature Chemical Biology, 2018, 14(12): 1118-1126.

[2]. Kugel S, Mostoslavsky R. Chromatin and beyond: the multitasking roles for SIRT6. Trends in Biochemical Sciences, 2014, 39(2): 72-81.

[3]. Tasselli L, Zheng W, Chua, K F. SIRT6: novel mechanisms and links to aging and disease. Trends in Endocrinology & Metabolism, 2017, 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.