2. Academic Validation
  3. Design, synthesis and biological evaluation of indazole derivatives as VEGFR-2 kinase inhibitors with anti-angiogenic properties

Design, synthesis and biological evaluation of indazole derivatives as VEGFR-2 kinase inhibitors with anti-angiogenic properties

  • Eur J Med Chem. 2024 Sep 19:279:116889. doi: 10.1016/j.ejmech.2024.116889.
Haoyu Zha 1,  Feilong Li 1,  Li Cai 2,  Wenhu Liu 1,  Manyu Zhang 1,  Shenglong Gu 1,  Hongyan Feng 1,  Zhenni Xia 1,  Chaohui Guo 1,  Xinjie Wu 1,  Chenxi Li 1,  Sufen Zhu 1,  Rong Li 3,  Jingbo Shi 4,  Xuesong Liu 5
Affiliations

Affiliations

  • 1 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China.
  • 2 Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, Anhui Province, PR China.
  • 3 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China. Electronic address: aydlirong@163.com.
  • 4 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China. Electronic address: sjbo616@126.com.
  • 5 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui Province, PR China. Electronic address: chemxsliu@126.com.
PMID: 39353237 DOI: 10.1016/j.ejmech.2024.116889
Abstract

The strategy of inhibiting angiogenesis, specifically by targeting vascular endothelial growth factor receptor 2 (VEGFR-2), has been proven effective in tumor treatment. In this study, we designed several VEGFR-2 kinase inhibitors based on an indazole scaffold. Among them, the most potent compound, 30, inhibits VEGFR-2 (IC50 = 1.24 nM) with subtle selectivity over other kinases. It demonstrates significant inhibitory activity against HUVEC angiogenesis and inhibits cell migration in a dose-dependent manner. Additionally, it exhibits low acute toxicity in mice. In vivo studies, compound 30 demonstrates favorable pharmacokinetic profiles. It suppresses tumor angiogenesis in the zebrafish subintestinal vessel model, indicating that it may be a potential angiogenesis inhibitor for further development.

Keywords

Anti-angiogenic; Indazole derivatives; VEGFR-2; Zebrafish.

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