Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scaffold Repurposing Approach.

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Fibroblast Growth Factor Receptors (FGFRs) are key regulators of cellular processes.
• Aberrant FGFR2 and FGFR3 signaling drives cancers like cholangiocarcinoma and bladder cancer.
• Current FGFR inhibitors cause adverse events by inhibiting FGFR1 and FGFR4.

Purpose of the Study:

• To discover selective FGFR2/FGFR3 inhibitors with reduced off-target activity.
• To develop novel cancer therapeutics with improved safety profiles.
• To identify orally bioavailable inhibitors targeting wild-type and mutant FGFRs.

Main Methods:

• Scaffold repurposing of an ALK2 inhibitor.
• Structure-based drug design.
• Structure-activity relationship (SAR) studies.

Main Results:

• Discovery of potent dual FGFR2/FGFR3 inhibitors.
• Achieved selectivity, sparing FGFR1 and FGFR4.
• Identified orally bioavailable compounds active against wild-type and gatekeeper mutant kinases.

Conclusions:

• Developed novel, selective FGFR2/FGFR3 inhibitors.
• These compounds show promise for improved cancer treatment with reduced toxicity.
• The findings support further development of these inhibitors for clinical application.