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Sirtuin 6(SIRT6),a member of the sirtuin family,is a nicotinamide adenine dinucleotide(NAD+)-dependent deacetylase that is involved in various physiological and pathological processes.SIRT6 is generally downregulated and linked to tumorigenesis in non-small cell lung carcinoma(NSCLC),thus regarded as a promising therapeutic target of NSCLC.In this study,we investigated whether MDL-800,an allosteric activator of SIRT6,exerted antiproliferation effect against NSCLC cells in vitro and in vivo.We showed that MDL-800 increased SIRT6 deacetylase activity with an EC50 value of 11.0±0.3 μM;MDL-800(10-50 μM)induced dose-dependent deacetylation of histone H3 in 12 NSCLC cell lines.Treatment with MDL-800 dose dependently inhibited the proliferation of 12 NSCLC celllines with IC50 values ranging from 21.5 to 34.5 μM.The antiproliferation effect of MDL-800 was significantly diminished by SIRT6 knockout.Treatment with MDL-800 induced remarkable cell cycle arrest at the G0/G1 phase in NSCLC HCC827 and PC9 cells.Furthermore,MDL-800(25,50 μM)enhanced the antiproliferation of epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)in osimertinib-resistant HCC827 and PC9 cells as well as in patient-derived primary tumor cells,and suppressed mitogen-activated protein kinase(MAPK)pathway.In HCC827 cell-derived xenograft nude mice,intraperitoneal administration of MDL-800(80 mg·kg-1·d-1,for 14 days)markedly suppressed the tumor growth,accompanied by enhanced SIRT6-dependent histone H3 deacetylation and decreased p-MEK and p-ERK in tumor tissues.Our results provide the pharmacological evidence for future clinical investigation of MDL-800 as a promising lead compound for NSCLC treatment alone or in combination with EGFR-TKIs.