MDL-800 (MDL800)

MDL-800 (2275619-53-7) is an allosteric activator of SIRT6 (EC50 = 10.3 μM).1 It specifically activates the deacetylase (H3K9ac and H3K56ac) activity of SIRT6 – inactive against SIRT1,3,4 and HDACs 1-11 with 10x less activity against SIRT2,5,7. It inhibited the growth of human hepatocarcinoma cells (HCC) via the tumor suppressor deacetylase (H3K9ac and H3K56ac) via cell-cycle arrest and showed efficacy in a xenograft model of HCC. MDL-800 improved the genetic stability of old-murine-derived iPSCs via activation of NHEJ and BER DNA repair pathways suggesting promise in treating age-related diseases via iPSC-based therapies.2 MDL-800 inhibited the proliferation of 12 non-small cell lung carcinoma cell lines with IC50 values of 21.5 to 34.5 μM.3 It also enhanced the effects of EGFR kinase inhibitors in Osimertinib-resistant HCC827 and PC9 cells as well as in patient-derived primary tumor cells.3

[1] ZHIMIN HUANG. Identification of a cellularly active SIRT6 allosteric activator[J]. Nature chemical biology, 2018, 14 12: 1118-1126. DOI:10.1038/s41589-018-0150-0
[2] YU CHEN. The SIRT6 activator MDL-800 improves genomic stability and pluripotency of old murine-derived iPS cells[J]. Aging Cell, 2020, 19 8. DOI:10.1111/acel.13185
[3] JIA-LIN SHANG. MDL-800, an allosteric activator of SIRT6, suppresses proliferation and enhances EGFR-TKIs therapy in non-small cell lung cancer[J]. Acta Pharmacologica Sinica, 2020, 42 1: 120-131. DOI:10.1038/s41401-020-0442-2