奥西默替尼
T790米
化学
癌症研究
表皮生长因子受体抑制剂
药理学
生物化学
表皮生长因子受体
吉非替尼
医学
受体
埃罗替尼
作者
Aoxue Wang,Shuai Wen,Chengyong Wu,Junping Pei,Panpan Yang,Xin Wang,Shutong Li,Jiaxi Liu,Yuxi Wang,Guan Wang,Liang Ouyang
标识
DOI:10.1021/acs.jmedchem.3c01934
摘要
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 EGFRL858R/T790M and ACK1 might improve therapeutic efficacy and overcome resistance in lung cancers treatment. Here, we identified a EGFRL858R/T790M/ACK1 dual-targeting compound 21a with aminoquinazoline scaffold, which showed excellent inhibitory activities against EGFRL858R/T790M (IC50 = 23 nM) and ACK1 (IC50 = 263 nM). The cocrystal and docking analysis showed that 21a occupied the ATP binding pockets of EGFRL858R/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 EGFRL858R/T790M/ACK1, which is deserved as a potential lead for overcoming acquired resistance to osimertinib during the EGFR-targeted therapy.
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