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

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)-N-(diphenylmethyl)
quinoline-4-carboxamide (12q), which showed an EC1.5 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. 12q significantly inhibited
the proliferation and migration of pancreatic ductal adenocarcinoma
(PDAC) cells in vitro. It also markedly suppressed
the tumor growth in a PDAC tumor xenograft model. This compound showed
attractive pharmacokinetic properties. Overall, 12q could
be a good lead compound for the treatment of PDAC, and it is worthy
of further study.