Design,Synthesis And Biological Activity Of Novel Selective Non-covalent Small-molecule EGFR^T790M Inhibitors

Lung cancer is one of the most common cancer in the world,with about 1.8 million new cases each year.Over 80%of lung cancers are non-small cell lung cancer（NSCLC）.Epidermal growth factor receptor（EGFR）,as the most valuable targets for the treatment of NSCLC,plays an essential role in cancer cell proliferation,survival,adhesion,migration and differentiation.Gefitinib,first generation non-covalent EGFR inhibitors,had got good results for NSCLC patients with EGFR^L858R mutations.However,after 8-14 months,approximately 60%of patients occured the T790M mutation and developed resistance.Second-generation covalent EGFR inhibitors,such as afatinib and dacomitinib,were developed for NSCLC patients with EGFR^L858R mutations and T790M resistance mutation.However,these inhibitors lacked selectivity between T790M mutant and wild-type EGFR kinase(EGFR^WT)and had also a strong inhibitory activity on EGFR^WT while inhibiting EGFR^T790M,resulting in severe toxic side effect.Third-generation covalent EGFR inhibitors,such as osimertinib,had weaker inhibitory activity against EGFR^WT and had higher inhibitory activity and selectivity against EGFR^T790M,thus reducing toxic side effect due to inhibition of EGFR^WT.However,one-third of patients who received treatment occured C797S mutations and developed resistance.Therefore,it is necessary to develop novel non-covalent EGFR inhibitors.In order to obtain more effective and selective non-covalent EGFR^T790M inhibitors,the thesis took NOV which was reported by Novartis as lead compound.Designed and synthesized twenty five 2-aminobenzimidazole-based novel compounds.The target compounds were confirmed by ¹H NMR,¹³C NMR and HR-MS（ESI）.Then the thesis tested their inhibitory activities against EGFR^WT,EGFR^T790M/L858R kinase and anti-proliferative activities of A431 and NCI-1975 cells and used AZD9291 as positive control.The results showed that most target compounds displayed distinct inhibitory activities against EGFR^T790M/L858Rand NCI-1975.Among them,compound 6l showed the best inhibitory activity against EGFR^T790M/L858R with IC₅₀ of 45.6±18.8 nM,which was superior to lead compound NOV（136.7±9.1 nM）.And it demonstrated more than 219-fold selectivity over EGFR^T790M.6a,6e,6h,6i and 6p exhibited better inhibitory activities against human lung adenocarcinoma cell（NCI-H1975）,with IC₅₀ of 1.929±0.347μM,2.168±0.819μM,2.335±0.787μM,1.930±0.529μM and 2.129±0.247μM,which were superior to lead compound NOV（2.653±1.395μM）.