Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Fibroblast growth factor receptors (FGFRs) are frequently overexpressed in various cancers due to genetic alterations.
• FGFRs are recognized as crucial targets for cancer therapy.
• Existing multi-targeted tyrosine kinase inhibitors exhibit activity against FGFRs but often lack selectivity.

Purpose of the Study:

• To design and develop novel, selective FGFR inhibitors with reduced off-target effects.
• To identify a potent and orally available lead compound for FGFR-targeted cancer therapy.

Main Methods:

• Structure-activity relationship (SAR) studies were conducted on Ponatinib analogues.
• In vitro assays were used to evaluate inhibitory activity against FGFRs and kinase insert domain receptor (KDR).
• Antitumor activity was assessed in vivo using FGFR-amplificated xenograft models (H1581 and SNU-16).

Main Results:

• Novel Ponatinib analogues demonstrated high FGFR inhibitory activity.
• Compound 4 exhibited 50-100 fold in vitro selectivity for FGFR1-3 over KDR.
• Compound 4 displayed significant antitumor efficacy in preclinical models with FGFR amplification.

Conclusions:

• Selective FGFR inhibitors, such as compound 4, represent a promising therapeutic strategy for cancers driven by FGFR alterations.
• The developed lead compound warrants further investigation for clinical development.
• Targeting FGFRs with selective inhibitors may offer improved efficacy and reduced side effects compared to non-selective agents.