Add time:07/13/2019         Source:sciencedirect.com

Accumulating evidence suggests that fibroblast growth factor receptor 1 (FGFR1) is an attractive target in gastric cancer therapy. Based on our previous discovery of two non-ATP competitive FGFR1 inhibitors, A114 and A117, we designed and screened a series of compounds with the framework of bisaryl-1,4-dien-3-one. Among them, D12 and D15 exhibited the most potent FGFR1 inhibitory activity, which was ATP-independent. Furthermore, a quantitative structure-activity relationship analysis of 41 analogs demonstrated that the specific structural substitutions alter their bioactivities. Molecular docking and dynamics simulation analysis indicated the hydrophobic interaction at the FGFR1-D12/D15 interaction was dominant. Evaluation for anti-gastric cancer efficacy of D12 and D15 indicated effective inhibition of cell proliferation, apoptosis induction and cell cycle arrest. Thus, these two FGFR1 inhibitors have therapeutic potential in the treatment of gastric cancer, and this study provides will contribute to the rational design of novel non-ATP competitive FGFR1 inhibitors.

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