Targeting neddylation pathway has been recognized as an attractive anticancer therapeutic strategy, thus discovering potent and selective neddylation inhibitors is highly desirable. Our work reported the discovery of novel cinnamyl piperidine compounds and their antitumor activity in vitro and in vivo. Among these compounds, compound 4g was identified as a novel neddylation inhibitor and decreased the neddylation levels of cullin 1, cullin 3 and cullin 5. Mechanistic studies demonstrated that compound 4g could inhibit the migration ability of gastric cancer cells and induce apoptosis partly mediated by the Nrf2-Keap1 pathway. Furthermore, in vivo anti-tumor studies showed that 4g effectively inhibited tumor growth without obvious toxicity. Collectively, the cinnamyl piperidine derivatives could serve as new lead compounds for developing highly effective neddylation inhibitors for gastric cancer therapy.

靶向 neddylation 途径已被认为是一种有吸引力的抗癌治疗策略，因此非常需要发现有效和选择性的 neddylation 抑制剂。我们的工作报告了新型肉桂基哌啶化合物的发现及其在体外和体内的抗肿瘤活性。在这些化合物中，化合物4g被鉴定为一种新型 neddylation 抑制剂，可降低 cullin 1、cullin 3 和 cullin 5 的 neddylation 水平。机理研究表明，化合物4g可抑制胃癌细胞的迁移能力并诱导细胞凋亡，部分由Nrf2-Keap1 通路。此外，体内抗肿瘤研究表明，4g有效抑制肿瘤生长，无明显毒性。总的来说，肉桂基哌啶衍生物可以作为新的先导化合物，用于开发用于胃癌治疗的高效内酯化抑制剂。