A Glycoconjugated SIRT2 Inhibitor with Aqueous Solubility Allows Structure-Based Design of SIRT2 Inhibitors

Small molecule inhibitors for SIRT2, a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent protein lysine deacylases, have shown promise in treating cancer and neurodegenerative diseases. Developing SIRT2-selective inhibitors with better pharmacological properties is key to further realize the therapeutic potential of targeting SIRT2. One of the best SIRT2-selective inhibitors reported is a thiomyristoyl lysine compound called TM, which showed promising anticancer activity in mouse models without much toxicity to normal cells. The main limitations of TM, however, are the low aqueous solubility and lack of X-ray crystal structures to aid future drug design. Here, we designed and synthesized a glucose-conjugated TM (glucose-TM) analog with superior aqueous solubility. Although glucose-TM is not cell permeable, the excellent aqueous solubility allowed us to obtain a crystal structure of SIRT2 in complex with it. The structure enabled us to design several new TM analogs, one of which, NH4-6, showed superior water solubility and better anticancer activity in cell culture. The results of these studies provided important insights that will further fuel the future development of improved SIRT2 inhibitors as promising therapeutics for treating cancer and neurodegeneration.