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设计,合成和生物评估针对C797S突变的新型EGFR PROTACs

Yasheng Zhu^1,2,3, Xiuquan Ye^1,4, Yuxing Wu^1,4

¹State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

Journal of medicinal chemistry

|April 27, 2024

概括

新型蛋白质分解向嵌合体 (PROTACs) 有效降解表皮生长因子受体 (EGFR) 突变,克服由C797S突变引起的Osimertinib耐药性. 化合物C6表现出强大的降解和瘤抑制,为EGFR突变癌症提供了新的策略.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

在表皮生长因子受体 (EGFR) 中的C797S突变赋予了对Osimertinib的耐药性,限制了其临床疗效.
针对蛋白质分解的仿真体 (PROTACs) 是一种有前途的治疗策略,通过诱导蛋白质降解来克服耐药性.

研究的目的:

设计和合成针对EGFR突变的新型PROTAC,特别是针对C797S突变介导的Osimertinib耐药性.
评估这些PROTACs在降解EGFR突变体和抑制瘤生长方面的有效性.

主要方法:

基于一种新的EGFR抑制剂的新型PROTACs的设计和合成.
在癌症细胞系 (H1975-TM) 中评估PROTACs对EGFR突变 (例如,EGFR^{L858R/T790M/C797S}) 的降解疗效.
使用异种移植瘤模型进行体内研究,以评估抗瘤活性和安全性.

主要成果:

代表性化合物C6证明了EGFR^{L858R/T790M/C797S} (DC50 = 10.2 nM) 和EGFR^{Del19/T790M/C797S}的强烈降解.
化合物C6在H1975-TM异种移植模型中表现出显著的抗瘤功效.
机理学研究证实通过无素-蛋白酶体系统的降解.

结论:

新型PROTACs,以C6为例,有效地克服由EGFR C797S突变驱动的Osimertinib耐药性.
这些PROTAC为耐药EGFR突变非小细胞肺癌患者提供了潜在的新治疗途径.

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