T790米
奥西默替尼
表皮生长因子受体抑制剂
表皮生长因子受体
突变体
癌症研究
突变
药理学
癌症
化学
医学
吉非替尼
埃罗替尼
生物化学
内科学
基因
作者
Hualin Zhang,Ruliang Xie,Hawaa AI-furas,Yupeng Li,Qingxia Wu,Jian Li,Fang Xu,Tianfeng Xu
标识
DOI:10.1021/acsmedchemlett.1c00645
摘要
The tertiary epidermal growth factor receptor (EGFR) C797S mutation predominates in the acquired mutational resistance in cancer patients to third-generation EGFR inhibitors. Small-molecule inhibitors targeting the EGFR C797S mutation have been developed with good efficiency. However, these compounds may still induce new EGFR mutations to evade the inhibition pathway. One EGFR protein degrader based on an allosteric inhibitor has shown some benefits of degrading the EGFR L858R/T790M/C797S triple mutant. However, the degrader of the other important triple EGFR mutation Del19/T790M/C797S has not been reported. Here we present the design and synthesis of a series of EGFR proteolysis-targeting chimeras (PROTACs) that can rapidly and potently induce EGFR degradation in Ba/F3 cells expressing the EGFRDel19/T790M/C797S mutant. One representative compound 6h time- and dose-dependently induced EGFR degradation with a DC50 of 8 nM. It also showed good antiproliferation activity (IC50 = 0.02 μM) against Ba/F3-EGFRDel19/T790M/C797S cells. 6h may serve as a lead compound to develop therapeutic agents for the treatment of resistant non-small cell lung cancer patients with EGFR C797S mutants.
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