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高度优化的中枢神经系统透抑制剂EGFR Exon20插入突变的抑制剂

William McCoull¹, Clare Thomson¹, Erin Braybrooke¹

¹AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, U.K.

Journal of medicinal chemistry

|January 27, 2025

概括

研究人员开发了新的EGFR Exon20插入 (Ex20Ins) 抑制剂,化合物23和36,它们具有强效,选择性和脑透性. 这些抑制剂有效地向Ex20Ins突变体,同时省略野生型 (WT) EGFR,解决一个关键的临床需求.

科学领域:

药用化学医学化学
在瘤学瘤学.
药理学药理学是指药理学的学科.

背景情况:

皮肤上生长因子受体 (EGFR) 抑制剂已推进了癌症治疗.
对于向EGFR Exon20插入 (Ex20Ins) 突变的抑制剂,存在重大未满足的需求.
现有的疗法往往缺乏选择性,影响野生型 (WT) EGFR.

研究的目的:

发现和优化用于强效和选择性EGFR Ex20Ins抑制的新型化学系列.
为了开发能够透大脑的抑制剂,可以节省WT EGFR.
为了应对诸如阿尔代氧化酶 (AO) 代谢等挑战,并实现有利的药理动力学特性.

主要方法:

基于结构的药物设计被用来优化化合物.
两种化学序列,以太23和二36被探索.
结构-活性关系 (SAR) 研究指导优化功效,选择性和降低代谢.

主要成果:

乙23和36被确定为Ex20Ins突变的强大和选择性抑制剂.
化合物显示脑透性,并保持了对WT EGFR.的选择性差距.
优化成功降低了阿尔代氧化酶 (AO) 代谢,这是人类清除风险.

结论:

化合物23和36代表了对EGFR Ex20Ins驱动的癌症有前途的候选药物.
开发的抑制剂在临床前模型中显示出有效性,具有有利的安全边际.
这项工作促进了针对肺癌具有挑战性的子集的向治疗方法的开发.

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