Optimization of covalent pan-fibroblast growth factor receptor inhibitors for treating solid tumors

Aberrant activation of fibroblast growth factor receptors (FGFRs) due to gene rearrangements or fusions, single-nucleotide variants, and copy number amplifications has been linked to several human cancers. Therefore, FGFRs increasingly recognized as a significant cancer therapy target. We herein designed and synthesized a series of quinoline derivatives as new type II covalent pan-FGFRs inhibitors based on our previous pan-FGFRs I-5. Of which, 18 exhibited a significant improvement in prominent pan-tumor inhibitory activities when substantially inhibited the kinase activities of FGFRs (FGFR1: IC₅₀ = 5.70 nM, FGFR2: IC₅₀ = 2.37 nM, FGFR3: IC₅₀ = 3.78 nM, FGFR4: IC₅₀ = 7.67 nM). Additionally, 18 blocked cellular FGFR phosphorylation and exhibited highly potent anti-tumor efficacy in vitro. Moreover, in vivo pharmacokinetic profiles and the safety property of 18 were found to be excellent (F % = 41.70%). Nevertheless, Oral administration of 18 significantly suppressed the tumor growth of the HuH-7 (TGI = 92.71%; 60 mg/kg, QD), SNU-16 (TGI = 49.80%; 30 mg/kg, QD) and RT112 (TGI = 67.61%; 30 mg/kg, QD) xenograft mouse models without obvious changes in body weight.