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Discovery of INCB126503 as a Potent and Selective FGFR2/3 Inhibitor
Minh H Nguyen1, Anlai Wang1, Lisa Truong1
1Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.
ACS Medicinal Chemistry Letters
|June 18, 2025
Summary
A new drug, INCB126503, shows promise as a targeted therapy for cancers driven by Fibroblast Growth Factor Receptor (FGFR) mutations. It effectively targets FGFR2/3, including resistant forms, with improved selectivity and reduced side effects.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Aberrant Fibroblast Growth Factor Receptor (FGFR) signaling, particularly involving FGFR2 and FGFR3, is a key driver in various cancers such as cholangiocarcinoma and urothelial carcinoma.
- Current therapies targeting FGFR2/3 utilize pan-FGFR inhibitors, which can cause off-target toxicities by inhibiting FGFR1/4 and are susceptible to acquired resistance mutations.
Purpose of the Study:
- To report the discovery and preclinical characterization of INCB126503, a novel, selective inhibitor of FGFR2 and FGFR3.
- To evaluate the efficacy and safety profile of INCB126503 in preclinical cancer models.
Main Methods:
- Discovery and characterization of INCB126503, assessing its potency, isoform selectivity, and activity against gatekeeper mutants.
- In vivo studies to evaluate FGFR signaling suppression, tolerability (including hyperphosphatemia), and antitumor efficacy in xenograft models with FGFR3 alterations.
Main Results:
- INCB126503 is a potent, orally bioavailable inhibitor with high selectivity for FGFR2/3.
- The compound demonstrates equipotent activity against gatekeeper mutants, overcoming a common resistance mechanism.
- INCB126503 effectively suppressed FGFR signaling in vivo without causing hyperphosphatemia.
- Significant antitumor efficacy was observed in preclinical models with FGFR3 genetic alterations.
Conclusions:
- INCB126503 represents a promising next-generation FGFR2/3 inhibitor with a favorable selectivity and safety profile.
- Its ability to overcome resistance and target specific FGFR alterations offers potential for improved cancer treatment strategies.
