Design, synthesis and evaluation of novel pyrimidinylaminothiophene derivatives as FGFR1 inhibitors against human glioblastoma multiforme

  • Eur J Med Chem. 2023 Nov 15;260:115764. doi: 10.1016/j.ejmech.2023.115764.
Yong-Liang Li  1 ,  Long-Jia Yan  1 ,  Hui-Xiong Chen  2 ,  Ban-Kang Ruan  1 ,  Pascal Dao  3 ,  Zhi-Yun Du  4 ,  Chang-Zhi Dong  5 ,  Bernard Meunier  6
Affiliations
  • 1. School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, PR China.
  • 2. School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, PR China; Chemistry of RNA, Nucleosides, Peptides and Heterocycles, CNRS UMR8601, Université Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270, Paris, Cedex 06, France. Electronic address: [email protected].
  • 3. Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR7272, Nice, France.
  • 4. School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, PR China. Electronic address: [email protected].
  • 5. School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, PR China; Université Paris Cité, ITODYS, UMR 7086 CNRS, 75013, Paris, France.
  • 6. School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, PR China; Laboratoire de Chimie de Coordination du CNRS, 205 Route de Narbonne, 31077, Toulouse, Cedex, France.
PMID: 37651879 DOI: 10.1016/j.ejmech.2023.115764
Abstract

Vascular endothelial growth factor receptors (VEGFRs) have emerged as the most promising anti-angiogenic therapeutic targets for the treatment of recurrent glioblastomas (GBM). However, anti-VEGF treatments led to the high proportion of non-responder patients or non lasting clinical response and the tumor progression to the greater malignant stage. To overcome these problems, there is an utmost need to develop innovative anti-angiogenic therapies. In this study, we report the development of a series of new FGFR1 inhibitors. Among them, compound 4i was able to potently inhibit FGFR1 kinase activities both in vitro and in vivo. This compound displayed strong anti-angiogenic activity in HUVECs and anti-tumor growth and anti-invasion effects in U-87MG cell line. These results emphasize the importance of FGFR1-mediated signaling pathways in GBM and reveal that pharmacological inhibition of FGFR1 can enhance the anti-tumoral, anti-angiogenic and anti-metastatic efficiency against GBM. These data support targeting of FGFR1 as a novel anti-angiogenic strategy and highlight the potential of compound 4i as a promising anti-angiogenic and anti-metastatic candidate for GBM therapy.

Keywords
Anti-angiogenesis; FGFR1; Glioblastomas; Inhibitor; Metastasis.
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