The NAD⁺-dependent deacetylase SIRT6 is an emerging cancer drug target, whose inhibition sensitizes cancer cells to chemo-radiotherapy and has pro-differentiating effects. Here we report on the identification of novel SIRT6 inhibitors with a salicylate-based structure. The new SIRT6 inhibitors show improved potency and specificity compared to the hit inhibitor identified in an in silico compound screen. As predicted based on SIRT6 biological roles, the new leads increase histone 3 lysine 9 acetylation and glucose uptake in cultured cells, while blocking TNF-α production and T lymphocyte proliferation. Notably, the new SIRT6 inhibitors effectively sensitize pancreatic cancer cells to gemcitabine. Finally, studies of compound fingerprinting and pharmacokinetics defined the drug-like properties of one of the new SIRT6 inhibitors, potentially allowing for subsequent in vivo proof-of-concept studies. In conclusion, new SIRT6 inhibitors with a salicylate-like structure were identified, which are active in cells and could potentially find applications in disease conditions, including cancer and immune-mediated disorders.

NAD ⁺依赖性脱乙酰基酶SIRT6是新兴的癌症药物靶标，其抑制作用使癌细胞对化学放射疗法敏感，并具有促分化作用。在这里，我们报告基于水杨酸酯的结构的新型SIRT6抑制剂的鉴定。与计算机上鉴定的命中抑制剂相比，新型SIRT6抑制剂显示出更高的效价和特异性复合屏幕。正如基于SIRT6生物学作用所预测的那样，新的先导增加了培养细胞中组蛋白3赖氨酸9的乙酰化和葡萄糖摄取，同时阻止了TNF-α的产生和T淋巴细胞的增殖。值得注意的是，新型SIRT6抑制剂可有效地使胰腺癌细胞对吉西他滨敏感。最后，化合物指纹图谱和药代动力学的研究定义了一种新型SIRT6抑制剂的类药物特性，从而有可能进行后续的体内概念验证研究。总之，已鉴定出具有水杨酸酯样结构的新型SIRT6抑制剂，它们在细胞中具有活性，并可能在疾病状况中应用，包括癌症和免疫介导的疾病。