Abstract
Fibroblast growth factor receptor (FGFR) is a promising anticancer target. Currently, most FGFR inhibitors lack sufficient selectivity and have nonnegligible activity against kinase insert domain receptor (KDR), limiting their feasibility due to the serious side effects. Notably, compensatory activation occurs among FGFR1–4, suggesting the urgent need to develop selective pan-FGFR1–4 inhibitors. Here, we explored the antitumor activity of DW14383, a novel irreversible FGFR1–4 inhibitor. DW14383 exhibited equivalently high potent inhibition against FGFR1, 2, 3 and 4, with IC50 values of less than 0.3, 1.1, less than 0.3, and 0.5 nmol/L, respectively. It is a selective FGFR inhibitor, exhibiting more than 1100-fold selectivity for FGFR1 over recombinant KDR, making it one of the most selective FGFR inhibitors over KDR described to date. Furthermore, DW14383 significantly inhibited cellular FGFR1–4 signaling, inducing G1/S cell cycle arrest, which in turn antagonized FGFR-dependent tumor cell proliferation. In contrast, DW14383 had no obvious antiproliferative effect against cancer cell lines without FGFR aberration, further confirming its selectivity against FGFR. In representative FGFR-dependent xenograft models, DW14383 oral administration substantially suppressed tumor growth by simultaneously inhibiting tumor proliferation and angiogenesis via inhibiting FGFR signaling. In summary, DW14383 is a promising selective irreversible pan-FGFR inhibitor with pan-tumor spectrum potential in FGFR1–4 aberrant cancers, which has the potential to overcome compensatory activation among FGFR1–4.
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Acknowledgements
This work was supported by grants from the “Personalized Medicines --Molecular Signature-based Drug Discovery and Development” Strategic Priority Research Program of the Chinese Academy of Sciences (Nos. XDA12020000 and XDA12020103), the National Natural Science Foundation of China for Innovation Research Group (No. 81821005), the National Natural Science Foundation of China (No. 81773762), the Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning (2020CXJQ02).
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JD and JA conceived the project; JA supervised the project; MDD, YLW, YD, YMS and YCJ performed the research; MDD, YLW, XP, LLL and JA analyzed the data; JF, YMW and WHD contributed to DW14383 design and synthesis; MDD, XP and JA wrote the paper.
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Dai, Md., Wang, Yl., Fan, J. et al. DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo. Acta Pharmacol Sin 42, 1498–1506 (2021). https://doi.org/10.1038/s41401-020-00567-3
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DOI: https://doi.org/10.1038/s41401-020-00567-3
