Abstract
The fibroblast growth factor receptors (FGFRs) are increasingly considered attractive targets for therapeutic cancer intervention due to their roles in tumor metastasis and angiogenesis. Here, we identified a new selective FGFR inhibitor, C11, and assessed its antitumor activities. C11 was a selective FGFR1 inhibitor with an IC50 of 19 nM among a panel of 20 tyrosine kinases. C11 inhibited cell proliferation in various tumors, particularly bladder cancer and breast cancer. C11 also inhibited breast cancer MDA-MB-231 cell migration and invasion via suppression of FGFR1 phosphorylation and its downstream signaling pathway. Suppression of matrix metalloproteinases 2/9 (MMP2/9) was associated with the anti-motility activity of C11. Furthermore, the anti-angiogenesis activity of C11 was verified in endothelial cells and chicken chorioallantoic membranes (CAMs). C11 inhibited the migration and tube formation of HMEC-1 endothelial cells and inhibited angiogenesis in a CAM assay. In sum, C11 is a novel selective FGFR1 inhibitor that exhibits potent activity against breast cancer metastasis and angiogenesis.
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Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (grants 81173080, 81321092, 21236002 and 21302054), the National Basic Research Program of China (973 Program, 2010CB126100), the National High Technology Research and Development Program of China (863 Program, 2011AA10A207), the National Science & Technology Pillar Program (2009ZX09103–102), the Shanghai Committee of Science and Technology (grant 13ZR1453100) and the Fundamental Research Funds for the Central Universities.
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JD, HX, Y-fX, X-hQ and H-lL designed research; ZC, L-jT, B-yT, H-yL, XW, TZ and YC performed research; ZC, XW and X-wC contributed new reagents or analytic tools; HX and ZC analyzed data; HX and ZC wrote the paper.
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Chen, Z., Tong, Lj., Tang, By. et al. C11, a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor, suppresses breast cancer metastasis and angiogenesis. Acta Pharmacol Sin 40, 823–832 (2019). https://doi.org/10.1038/s41401-018-0191-7
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DOI: https://doi.org/10.1038/s41401-018-0191-7
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