Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy-Resistant L858R/T790M/C797S Mutant
Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy-Resistant L858R/T790M/C797S Mutant
复制标题
DOI：
10.1002/anie.201603736
复制
发表时间：
2016-08-26
影响因子：
16.6
通讯作者：
Laufer, Stefan
中科院分区：
文献类型：
--
作者：
Guenther, Marcel;Juchum, Michael;Laufer, Stefan
表皮生长因子受体（EGFR）抑制剂治疗非小细胞肺癌（NSCLC）因体细胞突变引起的获得性耐药而具有挑战性。第三代EGFR抑制剂被设计为通过与酶的Cys 797残基共价结合来克服耐药性，并且这些抑制剂对大多数临床相关的EGFR突变体有效。然而，这些最近的EGFR抑制剂对这种特定相互作用的高度依赖性意味着Cys 797的额外突变导致抑制活性差，这导致最初响应患者的肿瘤复发。新一代的不可逆和可逆突变型EGFR抑制剂具有很强的非共价结合特性，这些化合物对半胱氨酸突变的L 858 R/T790 M/C797 S EGFR表现出很高的抑制活性。
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 Cys797 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 Cys797 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.