Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy-Resistant L858R/T790M/C797S Mutant

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• 作者：Marcel Gü ; nther ; Michael Juchum ; Dr. Gerhard Kelter ; Prof. Dr. Heiner Fiebig and Prof. Dr. Stefan Laufer
• 刊名：Angewandte Chemie International Edition
• 出版年：2016
• 出版时间：August 26, 2016
• 年：2016
• 卷：55
• 期：36
• 页码：10890-10894
• 全文大小：1191K
• ISSN：1521-3773

文摘

The treatment of non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors is made challenging by acquired resistance caused by somatic mutations. Third-generation EGFR inhibitors have been designed to overcome resistance through covalent binding to the Cys 797 residue of the enzyme, and these inhibitors are effective against most clinically relevant EGFR mutants. However, the high dependence of these recent EGFR inhibitors on this particular interaction means that additional mutation of Cys 797 results in poor inhibitory activity, which leads to tumor relapse in initially responding patients. A new generation of irreversible and reversible mutant EGFR inhibitors was developed with strong noncovalent binding properties, and these compounds show high inhibitory activities against the cysteine-mutated L858R/T790M/C797S EGFR.