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

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Aberrant fibroblast growth factor receptor (FGFR) activation is implicated in various human cancers.
• FGFRs are increasingly recognized as critical therapeutic targets in oncology.
• Previous development of pan-FGFR inhibitors (I-5) provided a foundation for new drug design.

Purpose of the Study:

• To design and synthesize novel quinoline derivatives as type II covalent pan-FGFR inhibitors.
• To evaluate the inhibitory activity and anti-tumor efficacy of these new compounds.
• To assess the in vitro and in vivo pharmacological properties of the lead compound.

Main Methods:

• Synthesis of a series of quinoline derivatives.
• In vitro kinase inhibition assays to determine IC50 values for FGFR1-4.
• Cellular assays to assess FGFR phosphorylation inhibition.
• In vivo studies in xenograft mouse models to evaluate anti-tumor efficacy and pharmacokinetics.

Main Results:

• Compound 18 demonstrated potent inhibition of FGFR kinase activity (IC50 values in nanomolar range for FGFR1-4).
• Compound 18 effectively blocked cellular FGFR phosphorylation and showed strong in vitro anti-tumor activity.
• Excellent in vivo pharmacokinetic profiles and safety were observed for compound 18 (41.70% bioavailability).
• Oral administration of compound 18 significantly suppressed tumor growth in HuH-7, SNU-16, and RT112 xenograft models with high tumor growth inhibition (TGI).

Conclusions:

• The novel quinoline derivative 18 is a potent type II covalent pan-FGFR inhibitor.
• Compound 18 exhibits significant anti-tumor efficacy in vitro and in vivo.
• This compound demonstrates promising therapeutic potential for FGFR-driven cancers.