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  • br Conflicts of interest br Acknowledgment br Introduction T


    Conflicts of interest
    Introduction The prostaglandin e1 growth factor receptors (FGFRs) are a family members of receptor tyrosine kinase (RTK) that represent attractive therapeutic targets for anti-cancer therapy gaining more and more attention in recent years [1], [2]. This family members are comprised by FGFR1, FGFR2, FGFR3, and FGFR4, which share significant sequence homology [3]. Like other RTKs [4], [5], [6], each of the receptors consists of an extracellular ligand binding domain, a single transmembrane domain, and a cytosolic region with a split tyrosine kinase binding domain [7]. For signal transduction (Fig. 1), the extracellular fibroblast growth factors (FGFs) bind to a cell-surface FGFR in a ternary complex consisting of FGF, FGFR, and heparan sulfate proteoglycans (HPSG) [8]. Dimerization of the ternary FGF/FGFR/HPSG complex leads to a conformational shift in the FGFR structure, resulting in intermolecular transphosphorylation of the intracellular tyrosine kinase domain and carboxy-terminal tail [9]. Subsequent downstream signaling occurs through two main pathways via the intracellular receptor substrates FGFR substrate 2 (FRS2) and phospholipase Cγ (PLCγ), leading ultimately to upregulation of the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-Akt, diacylglycerol-Protein kinase C (DAG-PKC), and inositol trisphosphate (IP3)-Ca2+-releasing signaling pathways [10], [11]. The FGFR family tyrosine kinases serve as high affinity receptors for the FGFs that control cell proliferation, migration, apoptosis, and differentiation and are involved in both developmental and adult tissue homeostasis [12]. Besides, many cancer cell types have been recognized to overexpress FGFRs, which include breast cancer [13], lung cancer [14], gastric cancer [15], endometrial cancer [16], and so on. As for FGFRs playing such an important role in tumors progression, the crystal structures of these kinases have been confirmed and the binding models of ATP in complex with these kinases have been determined in order to understand their mechanism of actions [17], [18], [19], [20]. Besides, according to the binding features, a large number of FGFR inhibitors have been explored and meaningful clinical outcomes of these inhibitors have been acquired [21], [22], [23], [24], [25]. Many published articles have reviewed the development of FGFR inhibitors [26], [27], [28], [29], [30], however, the reports that specially highlight the co-crystal structures of FGFRs in complex with inhibitors have not been found. In consideration of their vital roles in the exploration of molecules' mechanism of actions and development of new drugs, we conclude the reported co-crystals of FGFRs complexed with the corresponding inhibitors herein, main focusing our attention on the binding models and the pharmacological activities of the inhibitors.
    Categorization of the binding models of FGFR inhibitors in complex with receptors The binding models of FGFR inhibitors in complex with receptors can be grouped as Asp-Phe-Gly (DFG)-in bindings, DFG-out bindings, and irreversible bindings. DFG is a conserved activation loop playing an important role in regulating kinase activity. Inhibitors binding as the DFG-in conformation are named as Type I inhibitors, Negative regulators are ATP-competitive inhibitors that bind to the active forms of kinases with the aspartate residue of the DFG motif facing into the active site of the kinase (Fig. 2a). Correspondingly, Type II inhibitors exhibit the DFG-out binding conformation, they bind to the inactive forms of kinase with the aspartate residue of the DFG motif protruding outward from the ATP-binding site of the kinase. Importantly, the DFG-out state opens a new allosteric pocket directly adjacent to the ATP binding pocket which facilitates inhibitor binding (Fig. 2b). Inhibitors with irreversible bindings tend to covalently bind with a reactive nucleophilic cysteine residue proximal to the ATP-binding site, resulting in the blockage of the ATP site and irreversible inhibition (Fig. 2c) [31], [32], [33].