Design, Synthesis, and Biological Evaluation of Dual Inhibitors of EGFR/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 and ACK1 might improve therapeutic efficacy and overcome resistance in lung cancers treatment. Here, we identified a EGFR/ACK1 dual-targeting compound with aminoquinazoline scaffold, which showed excellent inhibitory activities against EGFR (IC = 23 nM) and ACK1 (IC = 263 nM). The cocrystal and docking analysis showed that occupied the ATP binding pockets of EGFR and ACK1. Moreover, showed potent antiproliferative activities against the H1975 cells, MCF-7 cells and osimertinib-resistant cells AZDR. Further, showed significant antitumor effects and good safety in ADZR xenograft-bearing mice. Taken together, was a potent dual inhibitor of EGFR/ACK1, which is deserved as a potential lead for overcoming acquired resistance to osimertinib during the EGFR-targeted therapy.