In the current study,we discovered that several N-terminus-to-side chain cyclic tripeptides harboring the catalytic mechanismbased SIRT1/2/3 inhibitory warhead Nε-thioacetyl-lysine at their central positions exhibited a comparably strong inhibition(nM level)against the SIRT1/2-catalyzed Nε-acetyl-lysine deacetylation reactions.Their dual SIRT1/2 inhibitory action was also found to be stronger than that against SIRT3/5/6.Considering the previous demonstration that a SIRT1/2 dual inhibition could be instrumental to achieving an anti-cancer effect on those cancers retaining the wild-type tumor suppresser p53 protein,these compounds could be employed as leads for developing novel anti-cancer agents.