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Updated: Aug 22, 2025
Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
Discovery of Potent and Selective Inhibitors of Wild-Type and Gatekeeper Mutant Fibroblast Growth Factor Receptor
Artem Shvartsbart1, Jeremy J Roach2, Michael R Witten3
1Prelude Therapeutics, Wilmington, Delaware 19803, United States.
Abstract:
Upregulation of the fibroblast growth factor receptor (FGFR) signaling pathway has been implicated in multiple cancer types, including cholangiocarcinoma and bladder cancer. Consequently, small molecule inhibition of FGFR has emerged as a promising therapy for patients suffering from these diseases. First-generation pan-FGFR inhibitors, while highly effective, suffer from several drawbacks. These include treatment-related hyperphosphatemia and significant loss of potency for the mutant kinases. Herein, we present the discovery and optimization of novel FGFR2/3 inhibitors that largely maintain potency for the common gatekeeper mutants and have excellent selectivity over FGFR1. A combination of meticulous structure-activity relationship (SAR) analysis, structure-based drug design, and medicinal chemistry rationale ultimately led to compound 29, a potent and selective FGFR2/3 inhibitor with excellent in vitro absorption, distribution, metabolism, excretion (ADME), and pharmacokinetics in rat. A pharmacodynamic study of a closely related compound established that maximum inhibition of downstream ERK phosphorylation could be achieved with no significant effect on serum phosphate levels relative to vehicle.
Insights
Novel fibroblast growth factor receptor (FGFR) inhibitors targeting FGFR2/3 were developed to overcome limitations of earlier drugs. These new inhibitors maintain potency against common mutations and show improved selectivity, offering a promising cancer therapy with fewer side effects.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Fibroblast growth factor receptor (FGFR) signaling pathway dysregulation is linked to cancers like cholangiocarcinoma and bladder cancer.
- Small molecule FGFR inhibition is a therapeutic strategy, but first-generation inhibitors cause hyperphosphatemia and lose potency against mutant kinases.
Purpose of the Study:
- To discover and optimize novel FGFR2/3 inhibitors with improved efficacy and safety profiles.
- To develop inhibitors that retain potency against common FGFR gatekeeper mutants and exhibit selectivity over FGFR1.
Main Methods:
- Structure-activity relationship (SAR) analysis.
- Structure-based drug design.
- Medicinal chemistry optimization leading to compound 29.
- In vitro ADME and pharmacokinetic studies in rats.
- Pharmacodynamic studies assessing ERK phosphorylation and serum phosphate levels.
Main Results:
- Compound 29 demonstrated potent and selective inhibition of FGFR2/3.
- Excellent in vitro absorption, distribution, metabolism, and excretion (ADME) properties were observed.
- Pharmacokinetic studies in rats showed favorable profiles.
- A related compound achieved maximal downstream ERK phosphorylation inhibition without significant impact on serum phosphate levels.
Conclusions:
- Novel FGFR2/3 inhibitors were successfully developed, addressing limitations of first-generation drugs.
- Compound 29 represents a promising candidate for treating FGFR-driven cancers with potentially reduced side effects like hyperphosphatemia.
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