PO.CH01.03 · 化学
在EGFR突变型肺癌中靶向EGFR半胱氨酸775
Targeting EGFR cysteine 775 in EGFR mutant lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
通过osimertinib共价靶向EGFR半胱氨酸797是靶向治疗领域最成功的突破之一，从根本上改变了非小细胞肺癌（NSCLC）患者的治疗格局。然而，由C797突变驱动的耐药性仍是一项重大临床挑战。开发超越C797靶向的新型共价策略为下一代EGFR抑制剂提供了引人注目的机遇。我们首次证明，位于ATP结合口袋深处的半胱氨酸775可被合理设计的共价分子ZNL-3所触及，该分子在osimertinib耐药的小鼠模型中表现出强效疗效。为进一步增强对导致耐药突变的抵抗力，我们开发了一种双弹头、双齿化合物YNW-1，其同时共价靶向半胱氨酸775和797。YNW-1是首个在两个半胱氨酸上表现出平衡反应效率的分子，使单位点突变无法赋予耐药性。ZNL-3和YNW-1的发现代表了EGFR靶向药物开发的重大进展，进一步优化以实现临床转化是一项值得的策略。
查看英文原文 English abstract
Covalent targeting of EGFR cysteine 797 by osimertinib is one of the most successful breakthroughs in targeted therapy, fundamentally transforming the treatment landscape for non-small cell lung cancer (NSCLC) patients. However, resistance driven by mutation of C797 remains a major clinical challenge. Developing novel covalent strategies beyond C797 targeting presents a compelling opportunity for next-generation EGFR inhibitors. We first demonstrated that cysteine 775, located deep within the ATP-binding pocket, is accessible by a rationally designed covalent molecule ZNL-3, which exhibited strong efficacy in osimertinib-resistant mouse models. To further enhance resilience to resistance-causing mutations, we developed a dual-warhead, bident compound-YNW-1-which covalently targets both cysteine 775 and 797 simultaneously. YNW-1 is the first molecule to exhibit balanced reactive efficiency on both cysteines, rendering single-site mutations ineffective to confer resistance. The discovery of ZNL-3 and YNW-1 represents significant advancements in EGFR-targeted drug development, and further optimization toward clinical translation is a worthwhile strategy.
利益披露 Disclosure
J. Jiang, None..
Z. Li, None..
Y. Wang, None..
S. J. Collins, None..
F. H. Gottlieb, None..
M. J. Eck, None..
P. A. Jänne, None..
J. Che, None..
T. Zhang, None.