A novel non-ATP competitive FGFR1 inhibitor with therapeutic potential on gastric cancer through inhibition of cell proliferation, survival and migration
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Fibroblast growth factor receptor 1 (FGFR1), belonging to receptor tyrosine kinases (RTKs), possesses various biological functions. Over-expression of FGFR1 has been observed in multiple human malignancies. Hence, targeting FGFR1 is an attractive prospect for the advancement of cancer treatment options. Here, we present a novel small molecular FGFR1 inhibitor L16H50, which can inhibit FGFR1 kinase in an ATP-independent manner. It potently inhibits FGFR1-mediated signaling in a gastric cancer cell line, resulting in inhibition of cell growth, survival and migration. It also displays an outstanding anti-tumor activity in a gastric cancer xenograft tumor model by targeting FGFR1 signaling. These results show that L16H50 is a potent non-ATP-competitive FGFR1 inhibitor and may provide strong rationale for its evaluation in gastric cancer patients.
KeywordsGastric cancer Non-ATP competitive FGFR1 inhibitor Proliferation Survival Migration
This work was supported by the National Natural Science Foundation of China (Grant Nos. 81402839, 81473242 and 81272462) the ZheJiang Province Natural Science Fund of China (Grant Nos. LY17H160059, LY14H160044) and the Technology Foundation for Medical Science of Zhejiang Province (Grant Nos. 2012KYA129), Granted by the Opening Project of Zhejiang Provincial Top Key Discipline of Pharmaceutical Sciences.
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- 4.Cross MJ, Hodgkin MN, Roberts S, Landgren E, Wakelam MJ, Claesson-Welsh L (2000) Tyrosine 766 in the fibroblast growth factor receptor-1 is required for FGF-stimulation of phospholipase C, phospholipase D, phospholipase A(2), phosphoinositide 3-kinase and cytoskeletal reorganisation in porcine aortic endothelial cells. J Cell Sci 113:643–651PubMedGoogle Scholar
- 17.Eathiraj S, Palma R, Hirschi M, Volckova E, Nakuci E, Castro J, Chen CR, Chan TCK, France DS, Ashwell M (2011) A novel mode of protein kinase inhibition exploiting hydrophobic motifs of autoinhibited kinases: discovery of ATP-independent inhibitors of fibroblast growth factor receptor. J Bio Chem 286:20677–20687CrossRefGoogle Scholar
- 18.DeLano WL (2002) The PyMOL molecular graphics system. DeLano Scientific, San Carlos, USAGoogle Scholar
- 25.National Comprehensive Cancer Network (2015) NCCN guidelines: Gastric Cancers, version 1Google Scholar
- 31.Tsimafeyeu I, Bratslavsky G (2015) Fibroblast growth factor receptor 1 as a target for the therapy of renal cell carcinoma. Int Soc Cell 88:321–331Google Scholar