Abstract
Overexpression of fibroblast growth factor receptor 1 (FGFR1) is a common aberration in lung and breast cancers and has necessitated the design of drugs targeting FGFR1‐dependent downstream signaling and FGFR1 ligand binding. To date, the major group of drugs being developed for treatment of FGFR1‐dependent cancers are small‐molecule tyrosine kinase inhibitors; however, the limited specificity of these drugs has led to increasing attempts to design molecules targeting the extracellular domain of FGFR1. Here, we used the phage display technique to select cyclic peptides F8 (ACSLNHTVNC) and G10 (ACSAKTTSAC) as binders of the fibroblast growth factor 1 (FGF1)–FGFR1 interface. ELISA and in vitro cell assays were performed to reveal that cyclic peptide F8 is more effective in preventing the FGF1–FGFR1 interaction, and also decreases FGF1‐induced proliferation of BA/F3 FGFR1c cells by over 40%. Such an effect was not observed for BA/F3 cells lacking FGFR1. Therefore, cyclic peptide F8 can act as a FGF1–FGFR1 interaction antagonist, and may be suitable for further development for potential use in therapies against FGFR1‐expressing cancer cells.
Highlights
Overexpression of fibroblast growth factor receptor 1 (FGFR1) is a common aberration in lung and breast cancers and has necessitated the design of drugs targeting FGFR1-dependent downstream signaling and FGFR1 ligand binding
ELISA and in vitro cell assays were performed to reveal that cyclic peptide F8 is more effective in preventing the fibroblast growth factor 1 (FGF1)–FGFR1 interaction, and decreases FGF1induced proliferation of BA/F3 FGFR1c cells by over 40%
To maximize the chance that selected peptides bind on the ligand–receptor interface, in the last step of selection, FGFR1 binding phage clones were eluted with 100 molar excess of FGF1
Summary
Overexpression of fibroblast growth factor receptor 1 (FGFR1) is a common aberration in lung and breast cancers and has necessitated the design of drugs targeting FGFR1-dependent downstream signaling and FGFR1 ligand binding. In physiological conditions FGFR protein is responsible for regulation of many processes such as cell proliferation, migration, differentiation and survival [3] Due to their function, FGFRs can influence tumor growth and stimulate angiogenesis, either by aberrant signaling or by overexpression on a cancer cell’s surface [4]. Small-molecule inhibitors, mainly directed to the Abbreviations Cys, cysteine; ERK1/2, extracellular signal-regulated kinases 1/2; FDA, The Food and Drug Administration; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; Fmoc, fluorenylmethyloxycarbonyl protecting group; HRP, horseradish peroxidase; mAB, monoclonal antibody; PFU, plaque forming units; RT, room temperature; TMB, 3,30,5,50-tetramethylbenzidine. A recently described small-molecule inhibitor, SSR128129E, is a rare example of a small-molecule drug binding to the extracellular domain of FGFR and allosterically preventing its activation [11,12]
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