Effect Of Novel EGFR Inhibitor Against T790M Type Non Small Cell Lung Cancer

OBJECTIVE:From the 7 series of FCN epidermal growth factor receptor(epidermal growth factor receptor, EGFR) tyrosine kinase inhibitors(tyrosine kinase inhibitors, TKIs) to choose the obvious inhibitory effect of highly active and selective compounds in H1975 cell lines and A431 cell lines, and further evaluate its anti-tumor effect in vivo and in vitro.METHODS :(1) MTS method for non-small cell lung cancer(NSCLC)(T790M mutation) H1975 cells in vitro proliferation inhibition test of seven FCN series compounds screening, get strong antitumor activity of compounds.(2)MTS method continues to screen out better selectivity of compounds in human skin squamous carcinoma A431 cells(WT-EGFR).(3) Flow cytometry instrument measure the compounds effects H1975 cell cycle and apoptosis.(4) Wound-healing measure the effects of the compounds on the migration ability.(5) H1975 cells in nude mice transplantation tumor experiment was done to confirm the effect of compounds on tumor growth in vivo.RESULTS:(1) According to the proliferation assay, FCN12, FCN14 and FCN15 were selected, and the IC50 was(103.33±12.10),(115.17±7.69),(128.63±32.72) nmol · L-1 respectively.(2)The proliferation inhibition activity in vitro of both the FCN14 and FCN12 which screened by A431 cell proliferation assay comparable to that of the control drug AZD9291(IC50>2 μmol·L-1).(3)FCM showed they could arrested the cycle cell of H1975 in G1 phase and increased cell apoptosis(P<0.01).(4)The study of wound-healing showed they inhibited cell migration(P<0.05), with a concentration dependent.(5)The xenografts in vivo experimental results showed that FCN12 and FCN14 can obvious inhibit tumor growth and reduce tumor volume(P<0.01).CONCLUSIONS:Filtered the EGFR TKIs: FCN12 and FCN14, have significant anti-tumor activity to T790 M of EGFR mutation of NSCLCl in vitro and in vivo with good development prospect and market application value.