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  • 1400W dihydrochloride br General features of FGFRs and inhib


    General features of FGFRs and inhibitors
    Conclusion Given the critical role of FGFRs in the progression of tumors, the co-crystal structures of these kinases in complex with inhibitors are determined in order to clarify the mechanism of actions and explore new efficient inhibitors. This manuscript highlights the co-crystal structures of FGFRs in complex with inhibitors and the pharmacological activities of these inhibitors. As for the crystallization method is firstly well established [34], most of the reported co-crystal structures are FGFR1/inhibitor complexes. Meanwhile, in order to overcome drug resistance, irreversible FGFR4 inhibitors are successfully acquired utilizing the cysteines around the binding site. In addition, co-crystal structures of one inhibitor in complex with two or more receptors are got to compare the binding characteristics and the mechanism of actions, which provide novel insights for drug design. However, although the crystal structures of FGFR2 and FGFR3 have been reported, the co-crystals of these kinases in complex with inhibitors are few or none, which suggest a direction for further development.
    Conflict of interest
    Introduction The 1400W dihydrochloride
    growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiological processes, including embryogenesis, adult tissue homeostasis and wound healing [1], [2], [3]. Substantial evidence has been accumulated that the aberrant FGFR signaling is activated in diverse tumor types by genetic alterations including genetic amplifications, somatic mutations and translocations [4], [5], [6]. Moreover, the results of studies using preclinical models and patient biomarker validation have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting tumor metastasis as well as conferring resistance to anticancer therapies [7], [8], [9], [10], [11]. Consequently, the targeted inhibition of FGFRs is an attractive modality for cancer treatment. However, most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The lack of kinase selectivity of these inhibitors has the potential of causing significant side effects [12], [13], [14]. For example, their activity against VEGF receptor 2 (VEGFR2, KDR) is the likely source of grade 3/4 hypertension induction and dose-limiting toxicity of these inhibitors [15], [16]. The discovery of substances that selectively inhibit kinases is a difficult yet significant challenge [17], [18], [19], [20], [21], [22]. Ponatinib (AP24534, Fig. 1) is a multi-targeted tyrosine kinase inhibitor that exhibits potent inhibitory activity against many tyrosine kinases including Abl, Src, PDGFRα, FGFR1 and KDR with respective IC50 values of 0.37 nM, 2.5 nM, 2.6 nM, 1.2 nM and 3.7 nM [23], [24]. As can be seen by viewing the information in Fig. 1, changes in the nature of the heterocyclic ring system attached to the Ponatinib core structure alter the specificities of binding to various kinases. This feature has been used advantageously to uncover selective Bcr-Abl inhibitors, which do not suffer from drug resistance [25], [26], [27], [28], [29], as well as selective DDR1 [30] and Src inhibitors [31] (Fig. 1). In our group, compound 1 as an analogue of Ponatinib was identified for a potent FGFR1 inhibitor with an IC50 value of 1.2 nM and a weaker activity against KDR with an IC50 of 79.1 nM at the enzymatic level. While the activity of 1 against FGFR1 translocated KG1 cells is only modest (IC50 = 175.5 nM). A following structure activity relationship (SAR) investigation based on compound 1 led to the development of a promising, orally available substance 4 which displays a 50–100 fold in vitro selectivity for inhibition of FGFR1-3 over VEGFR1-2. In addition, biological evaluation of this substance 4 showed that it displays significant antitumor activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models.