Design, Synthesis, and Biological Evaluation of Dual Inhibitors of EGFR^L858R/T790M/ACK1 to Overcome Osimertinib Resistance in Nonsmall Cell Lung Cancers

Abstract

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 dualtargeting compound 21a with aminoquinazoline scaffold, which showed excellent inhibitory activities against EGFR L858R/T790M (IC 50 = 23 nM) and ACK1 (IC 50 = 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 EGFRtargeted therapy.

Retrosynthesis Zero: Self-Improving Global Synthesis Planning Using Reinforcement Learning

“…To demonstrate the application capabilities of ReSynZ in the synthesis of complex molecules, we randomly selected four target molecules from recent literature that have reported experimental synthesis routes for analysis. − Using ReSynZ and the 13k template data set, we successfully determined the synthetic pathways for these four molecules and compared them to the experimental routes. Two cases are displayed in Figure , while the other two are detailed in section 5 of SI.…”