2. Academic Validation
  3. Synthesis and anti-tumor activity of EF24 analogues as IKKβ inhibitors

Synthesis and anti-tumor activity of EF24 analogues as IKKβ inhibitors

  • Eur J Med Chem. 2018 Jan 20:144:218-228. doi: 10.1016/j.ejmech.2017.11.077.
Rong Jin 1,  Qiuxiang Chen 2,  Song Yao 3,  Encheng Bai 1,  Weitao Fu 3,  Ledan Wang 4,  Jiabing Wang 3,  Xiaojing Du 1,  Tao Wei 5,  Haineng Xu 6,  Chengxi Jiang 6,  Peihong Qiu 3,  Jianzhang Wu 7,  Wulan Li 8,  Guang Liang 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 4 Department of Gynecology and Obstetrics, The 2nd Affiliated Hospital of the Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 5 Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: weitao@wzmu.edu.cn.
  • 6 Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou Biomedical Innovation Center, Wenzhou University and Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 7 Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou Biomedical Innovation Center, Wenzhou University and Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: wjzwzmu@163.com.
  • 8 Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; College of Information Science and Computer Engineering, The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: lwlwzmu@163.com.
PMID: 29351887 DOI: 10.1016/j.ejmech.2017.11.077
Abstract

EF24 is an IKKβ inhibitor (IC50: 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 (IC50: 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.

Keywords

Anti-tumor activity; IKKβ inhibitor; Molecular docking; Synthesis.

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