Discovery of Potent Small-Molecule SIRT6 Activators: Structure–Activity Relationship and Anti-Pancreatic Ductal Adenocarcinoma Activity

Abstract

SIRT6 activation is thought to be a promising target for the treatment of many diseases, particularly cancer. Herein, we report the discovery of a series of new small-molecule SIRT6 activators. Structure-activity relationship analyses led to the identification of the most potent compound, 2-(1-benzofuran-2-yl)-<i>N</i>-(diphenylmethyl) quinoline-4-carboxamide (<b>12q</b>), which showed an EC_1.5 value of 0.58 ± 0.12 μM and an EC₅₀ value of 5.35 ± 0.69 μM against SIRT6-dependent peptide deacetylation in FLUOR DE LYS assay. It exhibited weak or no activity against other HDAC family members as well as 415 kinases, indicating good selectivity for SIRT6. <b>12q</b> significantly inhibited the proliferation and migration of pancreatic ductal adenocarcinoma (PDAC) cells <i>in vitro</i>. It also markedly suppressed the tumor growth in a PDAC tumor xenograft model. This compound showed attractive pharmacokinetic properties. Overall, <b>12q</b> could be a good lead compound for the treatment of PDAC, and it is worthy of further study.