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

Zhenxiong Gao; Tingting Fan; Linbo Chen; Mengchu Yang; Vincent Kam Wai Wong; Dawei Chen; Zijian Liu; Yaoyao Zhou; Weibin Wu; Zixuan Qiu; Cunlong Zhang; Yuan Li; Yuyang Jiang

doi:10.1016/j.ejmech.2022.114402

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. Epub 2022 Apr 29.

Authors

Zhenxiong Gao¹, Tingting Fan², Linbo Chen², Mengchu Yang³, Vincent Kam Wai Wong³, Dawei Chen⁴, Zijian Liu⁴, Yaoyao Zhou⁵, Weibin Wu⁴, Zixuan Qiu⁵, Cunlong Zhang⁶, Yuan Li⁷, Yuyang Jiang⁸

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 T_1/2 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.

MeSH terms

14-3-3 Proteins
Antineoplastic Agents* / chemistry
Apoptosis
Carboxylic Acids
Cell Line, Tumor
Cell Proliferation
Drug Design
Drug Screening Assays, Antitumor
Humans
Indoles
Liver Neoplasms* / drug therapy
Molecular Docking Simulation
Structure-Activity Relationship

Substances

14-3-3 Proteins
Antineoplastic Agents
Carboxylic Acids
Indoles
indole-2-carboxylic acid