Discovery of a Pyrrole-pyridinimidazole Derivative as Novel SIRT6 Inhibitor for Sensitizing Pancreatic Cancer Cells to Gemcitabine

Abstract

Abstract 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. Then, we found that 8a can inhibit the proliferation, induce cell apoptosis and sensitize pancreatic cancer cells to gemcitabine treatment both in pancreatic cancer cells and xenograft models. Mechanistically, 8a inhibited the cell proliferation and survival signaling pathways, such as PI3K/AKT/mTOR and ERK signal pathway, and markedly exacerbated DNA damage induced by gemcitabine. Overall, we demonstrate that 8a, a novel SIRT6 inhibitor, could be a promising potential drug candidate for pancreatic cancer treatment.