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
化学
癌症研究
药理学
点突变
突变
医学
生物化学
埃罗替尼
受体
吉非替尼
基因
作者
Tobias Grabe,Kirujan Jeyakumar,Janina Niggenaber,Tom Schulz,Sandra Koska,Silke Kleinbölting,Michael Edmund Beck,Matthias Müller,Daniel Rauh
标识
DOI:10.1021/acsmedchemlett.2c00514
摘要
Drug resistance mutations emerging during the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors represent a major challenge in personalized cancer treatment and require constant development of new inhibitors. For the covalent irreversible EGFR inhibitor osimertinib, the predominant resistance mechanism is the acquired C797S mutation, which abolishes the covalent anchor point and thus results in a dramatic loss in potency. In this study, we present next-generation reversible EGFR inhibitors with the potential to overcome this EGFR-C797S resistance mutation. For this, we combined the reversible methylindole-aminopyrimidine scaffold known from osimertinib with the affinity driving isopropyl ester of mobocertinib. By occupying the hydrophobic back pocket, we were able to generate reversible inhibitors with subnanomolar activity against EGFR-L858R/C797S and EGFR-L858R/T790M/C797S with cellular activity on EGFR-L858R/C797S dependent Ba/F3 cells. Additionally, we were able to resolve cocrystal structures of these reversible aminopyrimidines, which will guide further inhibitor design toward C797S-mutated EGFR.
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