Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Thoracic Surgery, The First Affiliated Hospital of Whenzhou Medical University, Wenzhou, Zhejiang, China.
Chem Biol Drug Des. 2019 Jul;94(1):1368-1377. doi: 10.1111/cbdd.13514. Epub 2019 Apr 22.
As NF-κB signaling pathway is constitutively activated in lung cancer, targeting NF-κB has a potential for the treatment. EF24 has been proved to be a NF-κB inhibitor with good antitumor activity, while whose toxicity possibly became one of the obstacles to enter into clinical application. In order to find high efficiency and low toxicity NF-κB inhibitors, EF24 was modified and 13d was screened out. It was proved that 13d possessed an effective combination of inhibiting NF-κB pathway and showing lower cytotoxicity on normal cells as well as less toxicity in acute toxicity experiment compared with the lead compound of EF24. In addition, 13d was found to inhibit cell vitality, arrest cell cycle in G2/M phase, promote cell apoptosis, and suppress the xenograft tumor growth. Furthermore, 13d was elucidated to induce pyroptosis developing from apoptosis, which was associated with the inhibition of NF-κB. Taken together, it was suggested that 13d was a potent antitumor agent.
由于 NF-κB 信号通路在肺癌中持续激活，因此靶向 NF-κB 具有治疗潜力。EF24 已被证明是一种具有良好抗肿瘤活性的 NF-κB 抑制剂，但毒性可能成为其进入临床应用的障碍之一。为了寻找高效低毒的 NF-κB 抑制剂，对 EF24 进行了修饰，并筛选出 13d。实验证明，13d 具有抑制 NF-κB 通路的有效组合，对正常细胞的细胞毒性较低，急性毒性实验毒性较小。此外，13d 被发现能抑制细胞活力，将细胞周期阻滞在 G2/M 期，促进细胞凋亡，并抑制异种移植肿瘤生长。此外，还发现 13d 通过抑制 NF-κB 诱导细胞发生与凋亡相关的细胞焦亡。综上所述，13d 是一种有效的抗肿瘤药物。
