2. Academic Validation
  3. Design, synthesis and antitumor evaluation of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein

Design, synthesis and antitumor evaluation of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein

  • Eur J Med Chem. 2022 Aug 5;238:114402. doi: 10.1016/j.ejmech.2022.114402.
Zhenxiong Gao 1,  Tingting Fan 2,  Linbo Chen 2,  Mengchu Yang 3,  Vincent Kam Wai Wong 3,  Dawei Chen 4,  Zijian Liu 4,  Yaoyao Zhou 5,  Weibin Wu 4,  Zixuan Qiu 5,  Cunlong Zhang 6,  Yuan Li 7,  Yuyang Jiang 8
Affiliations

Affiliations

  • 1 Department of Chemical Engineering, Tsinghua University, Beijing, 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, PR China.
  • 2 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, PR China; Department of Chemistry Southern University of Science and Technology, Shenzhen, 518055, PR China.
  • 3 Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
  • 4 Shenzhen Kivita Innovat Drug Discovery Inst, Shenzhen, 518057, PR China; Shenzhen Bay Bio-pharm Technology Co., Ltd, Shenzhen, 518057, PR China.
  • 5 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, PR China.
  • 6 Shenzhen Kivita Innovat Drug Discovery Inst, Shenzhen, 518057, PR China; Shenzhen Bay Bio-pharm Technology Co., Ltd, Shenzhen, 518057, PR China. Electronic address: zhcunl@126.com.
  • 7 The Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. Electronic address: liyuan@njmu.edu.cn.
  • 8 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, PR China; Department of Chemistry Southern University of Science and Technology, Shenzhen, 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, PR China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
PMID: 35525080 DOI: 10.1016/j.ejmech.2022.114402
Abstract

In this work, a series of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein were designed and synthesized for treatment of liver Cancer. After structural optimization for several rounds, C11 displayed a relatively better affinity with 14-3-3η, as well as the best inhibitory activities against several typical human liver Cancer cell lines, including Bel-7402, SMMC-7721, SNU-387, Hep G2 and Hep 3B cells. Compound C11 also displayed best inhibitory activity against chemotherapy-resistant Bel-7402/5-Fu cells. Besides, C11 was rather safe against hERG and possessed moderate T1/2 and CL values in liver microsomes. In anti-proliferation, trans-well and cell Apoptosis assays, C11 also showed its huge potential as a potent antitumor agent. Then, Western blot assay was conducted, following analyzed by molecular docking, the anti-proliferative mechanisms of this small-molecule inhibitor were revealed. Moreover, C11 was demonstrated to induce G1-S phase cell cycle arrest in liver Cancer cells.

Keywords

14-3-3η protein; Antitumor bioactivity; Drug design; Hepatocellular carcinoma; Novel target.

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