Jin Rong, Chen Qiuxiang, Yao Song, Bai Encheng, Fu Weitao, Wang Ledan, Wang Jiabing, Du Xiaojing, Wei Tao, Xu Haineng, Jiang Chengxi, Qiu Peihong, Wu Jianzhang, Li Wulan, Liang Guang
Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Department of Ultrasound, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Eur J Med Chem. 2018 Jan 20;144:218-228. doi: 10.1016/j.ejmech.2017.11.077. Epub 2017 Dec 7.
EF24 is an IKKβ inhibitor (IC: 72 μM) containing various anti-tumor activities. In this study, a series of EF24 analogs targeting IKKβ were designed and synthesized. Several IKKβ inhibitors with better activities than EF24 were screened out and B3 showed best IKKβ inhibitory (IC: 6.6 μM). Molecular docking and dynamic simulation experiments further confirmed this inhibitory effect. B3 obviously suppressed the viability of Hela229, A549, SGC-7901 and MGC-803 cells. Then, in SGC-7901 and MGC-803 cells, B3 blocked the NF-κB signal pathway by inhibiting IKKβ phosphorylation, and followed arrested the cell cycle at G2/M phase by suppressing the Cyclin B1 and Cdc2 p34 expression, induced the cell apoptosis by down-regulating Bcl-2 protein and up-regulating cleaved-caspase3. Moreover, B3 significantly reduced tumor growth and suppressed the IKKβ-NF-κB signal pathway in SGC-7901 xenograft model. In total, this study present a potential IKKβ inhibitor as anti-tumor precursor.
EF24是一种具有多种抗肿瘤活性的IKKβ抑制剂（IC：72 μM）。在本研究中，设计并合成了一系列靶向IKKβ的EF24类似物。筛选出了几种活性优于EF24的IKKβ抑制剂，其中B3表现出最佳的IKKβ抑制活性（IC：6.6 μM）。分子对接和动力学模拟实验进一步证实了这种抑制作用。B3明显抑制了Hela229、A549、SGC - 7901和MGC - 803细胞的活力。然后，在SGC - 7901和MGC - 803细胞中，B3通过抑制IKKβ磷酸化阻断NF - κB信号通路，并通过抑制细胞周期蛋白B1和Cdc2 p34的表达使细胞周期停滞在G2/M期，通过下调Bcl - 2蛋白和上调裂解的caspase3诱导细胞凋亡。此外，在SGC - 7901异种移植模型中，B3显著抑制肿瘤生长并抑制IKKβ - NF - κB信号通路。总之，本研究提出了一种潜在的IKKβ抑制剂作为抗肿瘤前体。
