2. Academic Validation
  3. Design, synthesis and evaluation of novel pyrimidinylaminothiophene derivatives as FGFR1 inhibitors against human glioblastoma multiforme

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

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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