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  • Over the last years the signaling pathways initialized by fi


    Over the last years, the signaling pathways initialized by fibroblast growth factors (FGFs) are found to be important for progression and development of several cancers11., 12., 13., 14.. To the best of our knowledge, currently 18 FGFs are identified in human genome, which regulated by four transmembrane FGF receptors to transduce the signal to intracellular components. FGFRs belong to the receptor tyrosine kinase family, and each composes of three extracellular immunoglobin type domains and intracellular kinase domain. Canonically, once the ligand bind to FGFR causes the dimerization and autophsphorylation, and activation. Helsten et al. analyzed frequencies of FGFR aberrations in 4853 solid tumors with next-generation sequencing, revealing that 7.1% of all tumor types have genetic alterations in the FGFFGFR axis, among them 49% affects FGFR1, 19% affects FGFR2 and 23% affects FGFR3. This, along with other evidences16., 17., reinforces that the FGFRs are promising targets for many types of cancer disease. Currently, the FGFR small-molecule inhibitors all targeted the ATP binding site in kinase domain, and are roughly classified into two types, non-selective FGFR inhibitors and selective FGFR inhibitors. As exemplified in Fig. 1, non-selective FGFR inhibitors are type-II kinase inhibitors, and usually associated with multi-kinase inhibitory activities, such as ponatinib which harbors potent activities at least for BCR-ABL, PDGFR, FGFR, VEGFR, and c-Src. However, recent trend focused on developing selective FGFR inhibitors that are thought to have better safety window, and two most advanced drug candidates are illustrated in Fig. 1. AZD4547, a potent FGFR1–3 inhibitor, showed strong inhibition on the FGFR downstream pathway and cytotoxic effects on multiple cell lines, including NSCLC E-4031 with FGFR1 amplification, gastric cancer (GC) cells carrying the FGFR2 amplification and endometrial cell line harboring the FGFR2-K310R/N550K mutations. Appealing clinical trial data from phase II proof-of-concept study also indicated its efficacy in patients with FGFR2 amplified GC (RR 33%), enabling the candidate advanced to phase III. Similarly, ARQ-087, an oral pan-FGFR inhibitor, is also in phase III study, holding the promise for the treatment of patients with FGFR alterations. In the present study, we reported our continuous effort on developing potent and selective FGFR inhibitors. Based on previous discoveries, we found 5-hydrosulfonyl-5H-pyrrolo[2,3-b]pyrazine (4) was an intriguing scaffold for FGFR inhibitors, as it can be used to install two parts of chemical groups, one for the back-pocket and another for the ribose pocket. And both of them are considered to be essential for selectivity. With the guidance of structure analysis, we rapidly optimized the enzymatic activity of this series to about 10 nmol/L. However, the poor in vitro metabolic stability of compounds in liver microsome and high P450 inhibition hinder the further evaluation. Based on the solved crystal structure and metabolite identification, we carried out the optimization and finally obtained inhibitor 35 through the in vivo pharmacokinetic study as the promising FGFR inhibitor. Further in vivo pharmacological study confirmed the utility of the compound.
    Results and discussion
    Conclusions Aberrant signaling of FGFFGFR axis was identified in many types of human cancers, which stimulates extensive efforts to develop inhibitors targeting the FGFR, a subfamily of receptor tyrosine kinases. Based on the hybrid approach and structure-based design, we combined a novel scaffold and a well-known FGFR-selectivity enhancing motif to quickly optimize the enzymatic activity to nmol/L range. With considerable efforts to improve the drug-like properties, we finally obtained a potent and in vivo active compound showing a promising sign for further development. Although there are several selective FGFR inhibitors currently being investigated in clinical trials, they may have different response to various mutated FGFR kinases. Also, acquired resistance to the kinase inhibitors make it inevitable to develop new chemotype inhibitors. Giving the novel binding mode of present disclosed FGFR inhibitors, it would be interesting to see whether it will have different utility in profiling the landscape of mutations of FGFRs, or it will play a different role in treating the acquired resistance coming along with other FGFR inhibitors.