Design and activity evaluation of new EGFR tyrosine kinase inhibitors containing cyclic polyamines

The EGFR-TK pathway is pivotal in non-small-cell lung cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFR^{del19/T790M/C797S}). Compound b demonstrated slightly improved inhibition activity against PC-9^{del19/T790M/C797S} (IC₅₀ = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.