The SIRT6 allosteric activatorMDL-800, identified using allosite tools, has shown therapeutic potentialin liver cancer. Steegborn et al. synthesizedand screened pyrrolo­[1,2-a]­quinoxaline derivatives,identifying the first synthetic SIRT6 activators, which effectivelyactivate SIRT6-dependent deacetylation of peptide substrates and completenucleosomes. Despite these advances,the development of SIRT3 activators remains challenging. Here, SIRT6 is linked to liver cancer.