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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
Next-generation isoform-selective fibroblast growth factor receptor inhibitors
1Chemical Biology Research Center, School of Pharmacy, Hangzhou Medical College, Hangzhou 310014, Zhejiang, China; Zhejiang Provincial Key Laboratory of Drug Discovery and Safety Evaluation for Inflammatory Chronic Diseases, Hangzhou Medical College, Hangzhou 310014, Zhejiang, China.
None:
Dysregulated fibroblast growth factor receptor (FGFR) signaling - driven by amplifications, mutations, or fusions - represents a clinically validated oncogenic driver across diverse malignancies. Pan-FGFR-selective inhibitors (erdafitinib, pemigatinib, and futibatinib) have been developed in clinical practice. However, their therapeutic efficacy is substantially limited by inevitable on-target resistance mutations and toxicities via FGFR1/4 inhibition. Next-generation FGFR isoform-selective small-molecule inhibitors are emerging and represent active research frontiers. FGFR2-selective inhibitor lirafugratinib, FGFR3-selective inhibitors LOXO-435 and TYRA-300, FGFR2/3-selective inhibitor ABSK061, and FGFR4-selective inhibitors are in clinical development. Additionally, novel isoform-selective FGFR-targeting degraders, FGFR2b/FGFR3-selective antibodies, and de novo-designed 'c' isoform-selective proteins provide novel treatment strategies. This review provides an overview of the current FGFR-targeted therapeutics and limitations and evaluates next-generation inhibitor development to guide future research.
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