Design And Activity Evaluation Of Small Molecule Tyrosine Kinase Inhibitors Modified By Cyclic Polyamines

Non small cell lung cancer（NSCLC）is a serious life-threatening disease,accounting for over 85%of all lung cancer cases.The epidermal growth factor receptor（EGFR）is an effective target for the treatment of NSCLC,but the C797S site resistance mutation renders all epidermal growth factor receptor inhibitors on the market ineffective.Currently,no fourth representative epidermal growth factor receptor inhibitor has been approved for use.Cyclopolyamines have been widely used in the field of anticancer therapy due to their ATP degradation ability.In this study,a series of novel small molecule tyrosine kinase inhibitors were designed and synthesized by combining cyclopolyamines with the mother nucleus structure of traditional epidermal growth factor receptor tyrosine kinase inhibitors（EGFR-TKIs）to achieve competitive inhibition of ATP binding tyrosine kinase domains and ATP hydrolysis.In the kinase activity inhibition experiment,the synthesized inhibitors exhibited varying degrees of inhibitory effects on EGFR L858R/T790M/C797S and EGFR DEL19/T790M/C797S three mutated kinases,with compound 8e having an IC₅₀of 0.649 and 0.849 n M,respectively.Simultaneously synthesized a series of cyclic polyamine modified inhibitors that are insensitive to EGFR wild-type(IC₅₀>5μM)Showing good selectivity.During the process of optimizing the inhibitor structure,it was found that the activity of the inhibitor was related to the size of the cyclic polyamine.The synthesized piperazine modified inhibitor achieved an IC₅₀of 89 n M for the Del19/T790M/C797S triple mutant EGFR.Subsequent ATP degradation experiments showed that these cyclic polyamine modified inhibitors can affect intracellular ATP levels at certain concentrations.Finally,this article also utilized molecular simulation docking tools to study the binding mode of inhibitors and tyrosine kinases.Therefore,the cyclic polyamine modified inhibitor studied in this article is expected to become a new fourth generation tyrosine kinase inhibitor through the synergistic effect of ATP degradation and competitive binding kinase domains.