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 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. 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.

中文翻译：

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强大的小分子SIRT6激活剂的发现：结构与活性的关系和抗胰腺导管腺癌的活性。

SIRT6激活被认为是治疗许多疾病，特别是癌症的有希望的靶标。在此，我们报告发现了一系列新的小分子SIRT6激活剂。结构-活性关系分析导致鉴定出最有效的化合物2-（1-苯并呋喃-2-基）-N-（二苯甲基）喹啉-4-甲酰胺（12q），EC _1.5值为0.58±在FLUOR DE LYS分析中，对SIRT6依赖性肽脱乙酰作用的0.12μM和EC ₅₀值为5.35±0.69μM。它对其他HDAC家族成员以及415种激酶显示弱或无活性，表明对SIRT6的选择性好。12q显著抑制增殖和胰腺导管腺癌（PDAC）细胞迁移的体外。它也显着抑制了PDAC肿瘤异种移植模型中的肿瘤生长。该化合物显示出有吸引力的药代动力学性质。总体而言，12q可能是治疗PDAC的良好先导化合物，值得进一步研究。