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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.