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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
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.
Abstract:
Fibroblast growth factor receptors (FGFRs) are well-established oncology targets, with aberrant FGFR2 and FGFR3 activation implicated in multiple tumor types, including cholangiocarcinoma and urothelial carcinoma. Currently approved FGFR2/3-targeted therapies rely on pan-FGFR small-molecule kinase inhibitors, which often lead to off-target toxicities due to unintended inhibition of FGFR1 and FGFR4, as well as acquired resistance driven by gatekeeper mutations. Herein, we report the discovery of INCB126503, a highly potent, orally bioavailable FGFR2/3 inhibitor with excellent isoform selectivity and equipotent activity against gatekeeper mutants. INCB126503 effectively suppresses FGFR signaling in vivo without inducing hyperphosphatemia and demonstrates significant antitumor efficacy in xenograft models harboring FGFR3 genetic alterations.
Insights
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.
