Ubiquitin-like protein neddylation is overactivated in various human cancers and correlates with disease progression, and targeting this pathway represents a valuable therapeutic strategy. Our previous work disclosed an antihypertensive agent, candesartan cilexetic (CDC), serves as a novel neddylation inhibitor for suppressing tumor growth by targeting Nedd8-activating enzyme (NAE). In this study, 42 benzimidazole derivatives were designed and synthesized based on lead compound CDC to improve the neddylation inhibition and anticancer efficacy. Optimal benzimidazole-derived 35 displayed superior neddylation inhibition in enzyme assay compared to CDC (IC₅₀ = 5.51 μM vs 16.43 μM), along with promising target inhibitory activity and killing selectivity in cancer cell. The results of cellular mechanism research combined with tumor growth suppression in human lung cancer cell A549 in vivo, accompanied with docking model, revealed that 35 has the potential to be developed as a promising neddylation inhibitor for anticancer therapy.

泛素样蛋白 neddylation 在各种人类癌症中过度激活，并与疾病进展相关，针对该途径代表了一种有价值的治疗策略。我们之前的工作公开了一种抗高血压药物坎地沙坦西酯（CDC），作为一种新型neddylation抑制剂，通过靶向Nedd8激活酶（NAE）来抑制肿瘤生长。本研究以先导化合物CDC为基础，设计合成了42种苯并咪唑衍生物，以提高neddylation抑制和抗癌功效。与 CDC 相比，最佳苯并咪唑衍生的35在酶测定中表现出优异的 neddylation 抑制作用（IC ₅₀ = 5.51 μM vs 16.43 μM），并且在癌细胞中具有有前途的靶点抑制活性和杀伤选择性。细胞机制研究结合人肺癌细胞A549体内肿瘤生长抑制的结果，并结合对接模型，揭示了35有潜力开发为有前景的neddylation抑制剂用于抗癌治疗。