新型苯并咪唑衍生的泛素化抑制剂的开发，用于抑制肿瘤的体外和体内生长。
Development of novel benzimidazole-derived neddylation inhibitors for suppressing tumor growth invitro and invivo.
机构信息
State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China.
Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
出版信息
Eur J Med Chem. 2021 Jan 15;210:112964. doi: 10.1016/j.ejmech.2020.112964. Epub 2020 Oct 24.
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 (IC = 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。我们之前的工作揭示了一种降压剂坎地沙坦西立酯（CDC），可作为一种新型的 neddylation 抑制剂，通过靶向 Nedd8-激活酶（NAE）抑制肿瘤生长。在这项研究中，基于先导化合物 CDC 设计和合成了 42 种苯并咪唑衍生物，以提高 neddylation 抑制和抗癌功效。优化的苯并咪唑衍生的 35 在酶测定中显示出比 CDC 更优异的 neddylation 抑制作用（IC = 5.51 μM 对 16.43 μM），同时在癌细胞中具有有前景的靶标抑制活性和杀伤选择性。细胞机制研究的结果以及体内人肺癌细胞 A549 的肿瘤生长抑制作用，结合对接模型，表明 35 有可能被开发为一种有前途的 neddylation 抑制剂，用于癌症治疗。
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