胰腺癌是一种高度侵袭性的癌症，主要以吉西他滨治疗，但其抗药性正在增加。作为SIRT6家族的一员，SIRT6在寿命和多种疾病（如癌症、糖尿病、炎症和神经退行性疾病）中发挥重要作用。考虑到SIRT6在细胞保护作用中的作用，它可能是一个潜在的抗癌药物靶点，并与抗癌治疗的抗性相关。然而，关于SIRT6抑制剂的报道很少。在这里，我们报告了一个新的非竞争性SIRT6抑制剂——吡咯-吡啶咪唑衍生物8a的发现，并研究了它在抗肿瘤活性和增敏胰腺癌对吉西他滨的作用和机制。首先，我们通过虚拟筛选发现了一种有效的SIRT6抑制剂化合物8a，并通过分子和细胞SIRT6活性测定进行了验证。8a在FLUOR DE LYS测定中对SIRT6脱乙酰化活性显示了IC50值为7.46±0.79μM，同时8a显著增加了细胞中H3的乙酰化水平。接着，我们发现8a能够抑制胰腺癌细胞的增殖并诱导细胞凋亡。我们进一步证明，8a通过逆转吉西他滨诱导的PI3K/AKT/mTOR和ERK信号通路的激活以及阻断DNA损伤修复通路，增敏胰腺癌细胞对吉西他滨的作用。此外，8a和吉西他滨的联合使用在胰腺癌异种移植模型中诱导出协同的抗肿瘤活性。总之，我们证明了8a作为一种新型SIRT6抑制剂，可能是胰腺癌治疗的有希望的潜在药物候选物。© 2023年，作者。

Pancreatic cancer is a highly aggressive cancer, and is primarily treated with gemcitabine, with increasing resistance. SIRT6 as a member of sirtuin family plays important roles in lifespan and diverse diseases, such as cancer, diabetes, inflammation and neurodegenerative diseases. Considering the role of SIRT6 in the cytoprotective effect, it might be a potential anticancer drug target, and is associated with resistance to anticancer therapy. However, very few SIRT6 inhibitors have been reported. Here, we reported the discovery of a pyrrole-pyridinimidazole derivative, 8a, as a new non-competitive SIRT6 inhibitor, and studied its roles and mechanisms in the antitumor activity and sensitization of pancreatic cancer to gemcitabine. Firstly, we found a potent SIRT6 inhibitor compound 8a by virtual screening and identified by molecular and cellular SIRT6 activity assays. 8a could effectively inhibit SIRT6 deacetylation activity with IC50 values of 7.46 ± 0.79 μM in FLUOR DE LYS assay, and 8a significantly increased the acetylation levels of H3 in cells. Then, we found that 8a could inhibit the cell proliferation and induce cell apoptosis in pancreatic cancer cells. We further demonstrate that 8a sensitize pancreatic cancer cells to gemcitabine via reversing the activation of PI3K/AKT/mTOR and ERK signaling pathways induced by gemcitabine and blocking the DNA damage repair pathway. Moreover, combination of 8a and gemcitabine induces cooperative antitumor activity in pancreatic cancer xenograft model in vivo. Overall, we demonstrate that 8a, a novel SIRT6 inhibitor, could be a promising potential drug candidate for pancreatic cancer treatment.© 2023. The Author(s).