Discovery and Structural Optimization of Novel Quinolone Derivatives as Potent Irreversible Pan-Fibroblast Growth...

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Aberrant activation of fibroblast growth factor receptors (FGFRs) drives multiple cancer types, establishing FGFRs as a critical therapeutic target.
• Renewed interest in irreversible inhibitors has spurred efforts to develop novel agents targeting FGFRs.

Purpose of the Study:

• To discover and optimize novel quinolone-based covalent pan-FGFR inhibitors.
• To evaluate the efficacy and selectivity of the lead compound I-5 in preclinical cancer models.

Main Methods:

• Molecular docking guided optimization of a lead compound (lenvatinib).
• In vitro kinase inhibition assays and cell proliferation assays (Huh-7, Hep3B HCC cells).
• In vivo pharmacokinetic studies and tumor growth inhibition (TGI) in xenograft mouse models (Huh-7, NCI-H1581).
• Liquid chromatography and tandem mass spectrometry (LC-MS/MS) for irreversible binding characterization.

Main Results:

• Discovery of novel quinolone-based covalent pan-FGFR inhibitors, with compound I-5 as a representative.
• I-5 demonstrated potent inhibition against FGFR1-4 (nanomolar activity) and suppressed HCC cell proliferation.
• I-5 exhibited high selectivity against 369 kinases and confirmed irreversible binding to target proteins.
• I-5 showed favorable in vivo pharmacokinetic properties and significant tumor growth inhibition in preclinical models.

Conclusions:

• Novel quinolone-based covalent pan-FGFR inhibitors, exemplified by I-5, represent a promising therapeutic strategy for FGFR-driven cancers.
• Compound I-5 displays potent and selective irreversible inhibition of FGFRs with significant efficacy in preclinical models.
• Further investigation of I-5 is warranted for its potential as an anticancer agent.