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.

胰腺癌是一种高度侵袭性的癌症，主要采用吉西他滨治疗，且耐药性不断增加。SIRT6作为sirtuin家族的一员，在生命周期和多种疾病中发挥着重要作用，例如癌症、糖尿病、炎症和神经退行性疾病。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，并且与抗癌治疗的耐药性相关。然而，SIRT6抑制剂的报道很少。在此，我们报道了吡咯-吡啶咪唑衍生物8a作为一种新型非竞争性SIRT6抑制剂的发现，并研究了其在抗肿瘤活性和胰腺癌对吉西他滨增敏中的作用和机制。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活性测定进行鉴定。8a可有效抑制SIRT6脱乙酰化活性，在FLUOR DE LYS测定中IC ₅₀值为7.46 ± 0.79 μM，并且8a显着增加细胞中H3的乙酰化水平。然后，我们发现8a可以抑制胰腺癌细胞的细胞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 信号通路的激活并阻断 DNA 损伤修复通路，使胰腺癌细胞对吉西他滨敏感。此外，8a 和吉西他滨的组合在体内胰腺癌异种移植模型中诱导协同抗肿瘤活性。总体而言，我们证明 8a 这种新型 SIRT6 抑制剂可能成为治疗胰腺癌的有前途的潜在候选药物。