1. Academic Validation
  2. Discovery of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives as novel anti-cancer agents targeting Nur77

Discovery of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives as novel anti-cancer agents targeting Nur77

  • Eur J Med Chem. 2022 Dec 15:244:114849. doi: 10.1016/j.ejmech.2022.114849.
Jingbo Qin 1 Xiaohui Chen 1 Weihao Liu 1 Jun Chen 1 Weirong Liu 1 Yongzhen Xia 1 Zhehui Li 1 Mingyu Li 1 Shaojuan Wang 2 Quan Yuan 2 Yingkun Qiu 3 Zhen Wu 4 Meijuan Fang 5
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China.
  • 2 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health & School of Life Science, Xiamen, 361102, China.
  • 3 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China. Electronic address: qyk@xmu.edu.cn.
  • 4 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China. Electronic address: wuzhen@wmu.edu.cn.
  • 5 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Science, Xiamen University, Xiamen, 361102, China. Electronic address: fangmj@xmu.edu.cn.
Abstract

Encouraged by our previous findings and in continuation of our ongoing study project in designing and synthesis of novel Nur77-targeting anti-cancer agents, a series of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives were designed, synthesized and biologically evaluated as potent Nur77 modulators. Among synthesized compounds, 8b maintained good potency against different liver Cancer cell lines and Other types of Cancer cell lines while exhibiting lower toxicity than the positive compound celastrol. Moreover, 8b displayed excellent Nur77-binding activity, superior to the lead compound 10g and comparable to the reference compound celastrol. The cytotoxic action of 8b towards Cancer cells was associated with its induction of Nur77-mitochondrial targeting and Nur77-dependent Apoptosis. Notably, 8b has good in vivo safety and anti-hepatocellular carcinoma (HCC) activity. Altogether, this study reveals that 8b is a novel Nur77 modulator with great promise for further research.

Keywords

Anticancer activity; Apoptosis; Indole derivatives; Nur77 ligand.

Figures