The fibroblast growth factor receptors (FGFRs) are a family of highly conserved transmembrane tyrosine kinases (RTKs), which constitute four members (FGFR1-4). Over the past decades, several genomic alterations in the FGF-FGFR axis including activation mutations, gene amplifications, and chromosomal translocations have been identified in a broad spectrum of human tumors as oncogenic drivers, thus offering a new strategy to develop molecular targeted personalized medicine based on the FGFR activation status in cancer patients. On the other hand, it is known that tumor angiogenesis is augmented by cross-talking between FGF ligands, VEGFRs, and inflammatory mediators in tumor stroma, and the synergistic effects of FGFs and VEGFs in tumor angiogenesis have been observed in preclinical studies. Therefore, compared to the previous multi-target FGFR inhibitors with less potency against FGFR, development of selective FGFR/VEGFR2 dual inhibitors with equal or even greater potency against FGFR would be an appealing combination. Starting from the phase II clinical FGFR inhibitor lucitanib (2), we conducted a medicinal chemistry approach by opening the central quinoline skeleton coupled with a scaffold hopping process thus leading to a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives. Compound 25a was identified to show selective and equally high potency against FGFR1/2 and VEGFR2 with IC50 values less than 5.0 nM. Significant antiproliferative effects on both FGFR1/2 and VEGFR2 addictive cancer cells were observed. In the SNU-16 xenograft model, compound 25a showed tumor growth inhibition rates of 25.0% and 81.0% at doses of 10 mg/kg and 50 mg/kg, respectively, without obvious body weight loss. In view of the synergistic potential of FGFs and VEGFs in tumor angiogenesis observed in preclinical studies, the FGFR/VEGFR2 dual inhibitor 25a may achieve better clinical benefits.

Design, synthesis and biological evaluation of a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives as potent fibroblast growth factor receptor (FGFR) inhibitors

256th National Meeting (2018)

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