Structural Mechanism and Inhibitors Targeting EGFR Exon 20 Insertion (Ex20ins) Mutations,Journal of Medicinal Chemistry

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Structural Mechanism and Inhibitors Targeting EGFR Exon 20 Insertion (Ex20ins) Mutations
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-09-05 , DOI: 10.1021/acs.jmedchem.3c00875
Hao Chen ₁ , Shiliang Hu ₁ , Adam V Patterson _{2,

3} , Jeff B Smaill _{2,

3} , Ke Ding _{1,

4} , Xiaoyun Lu ₁

Affiliation

Epidermal growth factor receptor (EGFR) targeted therapy is one of the most important and effective strategies to combat EGFR mutant nonsmall-cell lung cancer (NSCLC). However, a substantial number of patients bearing EGFR exon 20 insertion (Ex20ins) mutations respond poorly to common EGFR targeted therapies. This clinical need remained unmet until recently, when the EGFR Ex20ins mutation inhibitor mobocertinib was approved by the FDA. Despite this progress, the structural mechanisms of EGFR Ex20ins mutation resistance and characterization of inhibitor binding modes have not been systematically summarized. Herein, we analyze the structural mechanisms for ligand binding and resistance and summarize recent developments for the reported inhibitors of EGFR Ex20ins mutations. Furthermore, this Perspective aims to provide insights for the design of the next generation of EGFR Ex20ins inhibitors.

中文翻译：

针对 EGFR 外显子 20 插入 (Ex20ins) 突变的结构机制和抑制剂

表皮生长因子受体（EGFR）靶向治疗是对抗EGFR突变非小细胞肺癌（NSCLC）最重要、最有效的策略之一。然而，大量携带 EGFR 外显子 20 插入 (Ex20ins) 突变的患者对常见 EGFR 靶向治疗反应不佳。这一临床需求直到最近 EGFR Ex20ins 突变抑制剂 mobocertinib 获得 FDA 批准才得到满足。尽管取得了这些进展，但 EGFR Ex20ins 突变抗性的结构机制和抑制剂结合模式的表征尚未系统总结。在此，我们分析了配体结合和耐药的结构机制，并总结了已报道的 EGFR Ex20ins 突变抑制剂的最新进展。此外，本观点旨在为下一代 EGFR Ex20ins 抑制剂的设计提供见解。

更新日期：2023-09-05

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