Design, Synthesis, and Biological Evaluation of Dual Inhibitors of EGFRL858R/T790M/ACK1 to Overcome Osimertinib Resistance in Nonsmall Cell Lung Cancers

Activation of the alternative pathways and abnormal signaling transduction are frequently observed in third-generation EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors)-resistant patients. Wherein, hyperphosphorylation of Ack1 contributes to EGFR-TKIs acquired resistance. Dual inhibition of EGFR^L858R/T790M and Ack1 might improve therapeutic efficacy and overcome resistance in lung cancers treatment. Here, we identified a EGFR^L858R/T790M/Ack1 dual-targeting compound 21a with aminoquinazoline scaffold, which showed excellent inhibitory activities against EGFR^L858R/T790M (IC₅₀ = 23 nM) and Ack1 (IC₅₀ = 263 nM). The cocrystal and docking analysis showed that 21a occupied the ATP binding pockets of EGFR^L858R/T790M and Ack1. Moreover, 21a showed potent antiproliferative activities against the H1975 cells, MCF-7 cells and osimertinib-resistant cells AZDR. Further, 21a showed significant antitumor effects and good safety in ADZR xenograft-bearing mice. Taken together, 21a was a potent dual inhibitor of EGFR^L858R/T790M/Ack1, which is deserved as a potential lead for overcoming acquired resistance to osimertinib during the EGFR-targeted therapy.