Other than epidermal growth factor receptor (EGFR) tyrosine kinase (TK) signaling pathway, the paracrine activation of the EGFR pathway is a leading EGFR-TKIs resistance of non-small cell lung cancer (NSCLC).Fibroblast growth factor(FGF) signaling could function in an autocrine manner to promote NSCLC cell proliferation and resistance to chemotherapy.PD173074 is currently the only high-affinity reversible FGFR inhibitor;it is the preferred FGFR-ATP competitive inhibitor to inhibit FGFR kinase activity and to overcome the resistance of EGFR-TKIs.PD173074 also exists in many defects of reversible inhibitors: cells with high concentrations of ATP competition causes performance degradation and increase blood clearance rate.This paper aims to introduce PD173074 as the leading compound, constructs a suitable molecular docking model, designs and synthesis series of irreversible inhibitor of FGFRs(named IRTKIs) by incorporating an acrylamide moiety that forms a covalent bond with the Cys486 positioned in the P loop within the active site, and analyze pharmacodynamics binding capacity and binding specificity.This remarkable selectivity toward FGFRs indicates that the selectivity and potency of IRTKIs was determined primarily by noncovalent FGFR-drug interaction.The covalent linkage resulted in the irreversible blockage of FGFR1 activation and its downstream signals, which could potentially be advantageous in achieving efficacious in vivo action.But, more notably, the ability of IRTKIs to form a covalent bond resulted in a moderate inhibition of the gatekeeper mutant of FGFR1 that is resistant to the reversible inhibitor PD173074.This result suggests that irreversible FGFRinhibitors such as C2 should be considered promising leads to target FGFR mutants that may emerge in the clinic.