Design,Synthesis And Biological Activity Evaluation Of Kinase EGFR New Small-molecule Inhibitors

The epidermal growth factor receptor(EGFR),a receptor tyrosine kinase,is a key mediator in cellular signaling related to cell growth,proliferation,survival,and migration.Its aberrant activiy,including point mutations,deletions and insertions of amino acids at specific positions,plays a pivotal role in the onset and progression of cancers,which is the direct cause of a part of non-small cell lung cancer(NSCLC).In the past two decades,EGFR small molecule inhibitors have achieved great success in targeted therapy for non-small cell lung cancer and developed more than ten targeted drugs such as gefitinib,afatinib,and osimertinib.However,point mutations of target protein produced by the use of EGFR inhibitors are the primary causes of drug resistance.Therefore,it is of great significance to develop novel EGFR inhibitors that can effectively overcome the point mutations in existing drug resistance.In this study,we have developed a kinase-oriented focus compound library using thieno[3,2-d]opyrimidine and pyrrolo[3,2-d]pyrimidine as core scaffolds for targeting EGFR,especially for those drug resistant mutations.On the basis of AZD9291,89 compounds were designed and synthesized employing the scaffold hopping and bioactive fragment assembling strategy.The structure-activity relationship(SAR)study reveals the following structure features:(a)N-methyl hydrazine is favorable for EGFR kinase activity.(b)The para-substituent amines of the 2-position give better activity than the meta-aromatic amines.(c)The activity of the compound will be better when there is a larger substituent at the ortho position of the phenyl ring amino group,(d)Having N-methylpiperazine group is better than that of N-Boc piperazine.Although current synthesized compounds library did not yield highly potent inhibitors,these results provide important information to further optimize EGFR inhibitors with high potency and selectivity.