Abstract
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell membrane that play crucial roles in both developmental and adult cells. Dysregulation of FGFRs has been implicated in a wide variety of cancers, such as urothelial carcinoma, hepatocellular carcinoma, ovarian cancer and lung adenocarcinoma. Due to their functional importance, FGFRs have been considered as promising drug targets for the therapy of various cancers. Multiple small molecule inhibitors targeting this family of kinases have been developed, and some of them are in clinical trials. Furthermore, the pan-FGFR inhibitor erdafitinib (JNJ-42756493) has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic or unresectable urothelial carcinoma (mUC). This review summarizes the structure of FGFR, especially its kinase domain, and the development of small molecule FGFR inhibitors.
Highlights
The human fibroblast growth factor receptor (FGFR) family consists of four members: FGFR1 to FGFR4
In the FGF1/FGFR2/heparin crystal structure solved by Pellegrini et al, symmetric 2:2:2 stoichiometry ratio; both the FGF2 and heparin molecules simultaneously contacted the complex was assembled by asymmetric 2:2:1 stoichiometry [20]
Increasing evidence indicates that aberrant Fibroblast growth factor receptors (FGFR)signaling plays a crucial role in tumorigenesis and progression
Summary
The human fibroblast growth factor receptor (FGFR) family consists of four members: FGFR1 to FGFR4. Similar to other receptor tyrosine kinases (RTKs), FGFRs are expressed on the cell membrane and can be stimulated and activated by extracellular signals. The native ligand of FGFRs is fibroblast growth factors (FGFs) [2,3,4]. The binding of FGFs drives the dimerization of FGFRs; subsequently, a transautophosphorylation event of the intracellular kinase domain is induced, followed by the activation of downstream transduction pathways [5,6]. It is believed that small molecules that competitively bind to the adenosine triphosphate (ATP) pocket of aberrant FGFRs while exhibiting little or no toxicity provide limitless prospects for the treatment of relevant tumors. Into the understanding of inactivation of FGFRs for related disease therapy
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