NEDDylation process regulates multiple physiological functions and signaling pathways, which are still in an equilibrium that favors the survival and proliferation of tumor cells. Unlike inhibitors, NEDDylation agonists are rarely studied. In this work, novel 1,2,4-triazine-dithiocarbamate derivatives were synthesized and evaluated for antiproliferative activity against MGC-803, PC-3 and EC-109 cells. Among them, compound K3 displayed the most potent activity MGC-803, PC-3 and EC-109 cells with IC₅₀ values of 2.35, 5.71 and 10.1 μM, respectively, which were more potent than 5-FU. Further cellular mechanisms suggested that compound K3 inhibited the cell viability, induced proliferation inhibition, arrested cell cycle at G2/M phase and induced cell apoptosis in MGC-803 and HGC-27 cells. Importantly, compound K3 could interact with NAE1 to promote the NEDDylation of MGC-803 and HGC-27 cells. The promotion of NEDDylation resulted in the degradation of c-IAP and YAP/TAZ, which leads to the induction of cell apoptosis and inhibition of proliferation in MGC-803 and HGC-27 cells. Therefore, as a NEDDylation agonist, compound K3 could effectively inhibit gastric cancer cells. Here, we reported NEDDylation promotion induced by compound K3, which could inhibit the cancer cell lines MGC-803 and HGC-27 and induce the cancer cell apoptosis via prompting the degradation of c-IAP and YAP/TAZ.

NEDD化过程调节多种生理功能和信号通路，它们仍处于有利于肿瘤细胞存活和增殖的平衡状态。与抑制剂不同，NEDDylation 激动剂很少被研究。在这项工作中，合成了新型 1,2,4-三嗪-二硫代氨基甲酸酯衍生物，并评估了其对 MGC-803、PC-3 和 EC-109 细胞的抗增殖活性。其中，化合物K3对MGC-803、PC-3和EC-109细胞的活性最强，IC ₅₀值分别为2.35、5.71和10.1 μM，比5-FU更有效。进一步的细胞机制表明，化合物K3在MGC-803和HGC-27细胞中抑制细胞活力，诱导增殖抑制，使细胞周期停滞在G2 / M期并诱导细胞凋亡。重要的是，化合物K3可以与 NAE1 相互作用以促进 MGC-803 和 HGC-27 细胞的 NEDDylation。NEDDylation 的促进导致 c-IAP 和 YAP/TAZ 的降解，从而导致 MGC-803 和 HGC-27 细胞的细胞凋亡和增殖抑制。因此，作为NEDDylation激动剂，化合物K3可以有效抑制胃癌细胞。在这里，我们报道了由化合物K3诱导的 NEDDylation 促进作用，它可以抑制癌细胞株 MGC-803 和 HGC-27 并通过以下途径诱导癌细胞凋亡 促使 c-IAP 和 YAP/TAZ 降解。