发现和优化针对EGFR Exon20插入突变的强效,有效和选择性抑制剂
Clare Thomson1, Peter Barton1, Erin Braybrooke1
1AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom.
Journal of medicinal chemistry
|May 21, 2024
概括
研究人员发现了强大的EGFR Exon20插入抑制剂,其对野生类型EGFR具有很高的选择性. 化合物36对非小细胞肺癌 (NSCLC) 治疗具有潜在降低毒性的承诺.
科学领域:
- 药用化学 医学化学
- 在瘤学瘤学.
- 药物发现 药物发现 药物发现
背景情况:
- EGFR Exon20插入是一种罕见但具有攻击性的非小细胞肺癌 (NSCLC) 的子集.
- 现有的疗法往往对这些突变具有有限的疗效和显著的毒性.
研究的目的:
- 识别和优化针对EGFR Exon20插入的新型抑制剂.
- 为了实现高选择性超过野生类型的EGFR,以最大限度地减少非目标效应和毒性.
主要方法:
- 高通量选 (HTS) 活动.
- 基于结构的药物设计 (SBDD) 具有代优化.
- 链接器修改策略.链接器修改策略.
主要成果:
- 发现了一系列强效的野生型选择性EGFR Exon20插入抑制剂.
- 化合物36证明了EGFR Exon20插入的强大和选择性抑制.
- 化合物36在NSCLC异种移植中表现出令人鼓舞的疗效,其中包括SVD Exon20插入.
- 与CLN-081相比,化合物36在野生类型的EGFR异种移植中表现出较低的疗效,这表明与野生类型相关的毒性较低.
结论:
- 化合物36代表了具有EGFR Exon20插入的NSCLC患者有前途的治疗候选者.
- 开发的抑制剂显示出有利的选择性概况,可能导致更好的安全性和耐受性.
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