Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

Abstract

Targeted therapy is a groundbreaking innovation for cancer treatment. Among the receptor tyrosine kinases, the fibroblast growth factor receptors (FGFRs) garnered substantial attention as promising therapeutic targets due to their fundamental biological functions and frequently observed abnormality in tumors. In the past 2 decades, several generations of FGFR kinase inhibitors have been developed. This review starts by introducing the biological basis of FGF/FGFR signaling. It then gives a detailed description of different types of small-molecule FGFR inhibitors according to modes of action, followed by a systematic overview of small-molecule-based therapies of different modalities. It ends with our perspectives for the development of novel FGFR inhibitors.

Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents

“…Several tyrosine residues in FRS2 are phosphorylated after FGFR activation and serve as docking sites for the following molecules. 150 The RAS-MAPK-ERK signalling cascade is repeatedly activated by FRS2. RSA was chacterised by docking with different proteins, including SHP2 (SH2-containing tyrosine kinase phosphatase), GRB2 (growth factor receptor-bound protein 2), SOS (Son of Sevenless).…”

Discovery of potential FGFR3 inhibitors via QSAR, pharmacophore modeling, virtual screening and molecular docking studies against bladder cancer

“…In order to generate a pharmacophore model, the first 100 molecules related to fgfr3 gene were extracted from binding database ( https://www.bindingdb.org/bind/index.jsp ) according to their IC50 values. Four approved drugs that are effective in FGFR3 inhibition, namely Ponatinib (BD50322535), Nintedanib (BD50026612), Pemigatinib (BD86705695), and Infigratinib (BD50355393) was used along with the relevant conformers for benchmark datasets [ 26 , 27 ]. Schrödinger software version 2018 (Schrödinger, LLC, New York, NY) was used for modeling and screening of pharmacophore model.…”

Therapeutic angiogenesis based on injectable hydrogel for protein delivery in ischemic heart disease

“… 57 , 58 FGF-1, also known as acidic FGF or aFGF, and FGF-2, also known as basic FGF or basic fibroblast growth factor (bFGF), are endothelial cell mitogens that also act on smooth muscle cells and fibroblasts. 59 , 60 FGF promotes its binding to tyrosine kinase receptors through cell-surface heparan sulfate proteoglycans, induces endothelial cell proliferation, migration, and protease production, and participates in angiogenesis. 61 , 62 FGF stimulates the synthesis of proteases by EC, including plasminogen activators and metalloproteinases, which are critical for the digestion of the extracellular matrix during angiogenesis.…”