Development Of Novel Potent And Selective SIRT1/2 Dual Inhibitors

Sirtuins are a family ofβ-NAD⁺-dependent protein N^ε-acyl-lysine deacylases.Sirtuins are also evolutionarily conserved proteins that are present in all kingdoms of life ranging from bacteria to humans.Sirtuin family members include the mammalian sirtuins（SIRT1-7）,the bacterial sirtuins,the archaeal sirtuins（Sir2Af1 and Sir2Af2）,the parasitic sirtuins,and the yeast sirtuins.The sirtuin-catalyzed deacylation reaction has been demonstrated to play an important regulatory role in multiple crucial cellular processes such as transcription,DNA damage repair,and metabolism.Therefore this reaction has also been regarded as a potential therapeutic target for human diseases.Inhibitors of sirtuins are currently being targeted as potent therapeutic agents for human diseases such as cancer,neurodegenerative diseases,and other disorders.The sirtuin-catalyzed deacylation reaction has a unique mechanism:NAD⁺reacts with N^?-acyl-lysine as the co-substrate via a nucleophilic substitution reaction with the release of nicotinamide.And the deacylated product and 2’-O-acyl-adenosine diphosphate-ribose（2’-O-AADPR）are then generated with the participation of H₂O.During the past few years,a variety of chemical probes and modulators（inhibitors and activators）for the sirtuin deacylation reaction have been developed and some of them have been employed toward an enhanced mechanistic and functional（pharmacological）understanding of the sirtuin-catalyzed deacylation reaction,however,there has been no breakthrough in identifying potent and selective SIRT1/2 dual inhibitors.Therefore the aim of my study is to develop potent and selective SIRT1/2 dual inhibitors.Previous studies have demonstrated that SIRT1/2dual inhibition had significant anti-cancer effect for those cancers retaining the wild-type tumor suppresser p53 protein.First,we selected N^?-thioacetyl-lysine as the inhibitory warhead due to its efficacy.The overall structural scaffold of our compounds was a N terminus-to-side chain cyclic tripeptidic structure.We seeked to identify potent and selective SIRT1/2 dual inhibitors through the optimization of the lead compound.In the current study,we discovered that several N-terminus-to-side chain cyclic tripeptides harboring the catalytic mechanism-based SIRT1/2/3 inhibitory warhead N^ε-thioacetyl-lysine at their central positions exhibited a comparably strong inhibition（nM level）against the SIRT1/2-catalyzed N^ε-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.