发现KRAS ((G12D) 选择性降解剂ASP3082
Tomohiro Yoshinari1, Takeyuki Nagashima2, Hiroki Ishioka2
1Engineered Small Molecules, Astellas Pharma Inc., Tsukuba, Japan. tomohiro.yoshinari@astellas.com.
Communications chemistry
|August 23, 2025
概括
研究人员开发了ASP3082,一种针对癌症常见的KRAS (G12D) 突变的新型降解剂. 这种化合物有效降解KRAS(G12D) 蛋白质,有望治疗KRAS(G12D) 突变的癌症.
科学领域:
- 癌症学
- 分子生物学
- 药物发现
背景情况:
- 基尔斯鼠肉瘤病毒瘤基因同源 (KRAS) 是各种癌症中经常发生突变的瘤基因.
- KRAS ((G12D) 是最常见的KRAS突变,但与KRAS ((G12C) 不同,缺乏批准的向疗法.
研究的目的:
- 发现和描述ASP3082,一种向KRAS(G12D) 突变的选择性降解剂.
- 展示基于结构的优化方法,用于双功能近距离诱导药物.
主要方法:
- 发现和描述ASP3082,一个KRAS(G12D) 选择性降解剂.
- 确定KRAS ((G12D) /ASP3082/VHL三元复合物的晶体结构.
- 在KRAS ((G12D)) 突变癌症异种移植模型中评估ASP3082的疗效.
主要成果:
- ASP3082可以选择性地诱导KRAS ((G12D) 蛋白的降解.
- 这种药物具有强大而持久的药理活性.
- 在临床前的癌症模型中,ASP3082治疗导致了显著的瘤回归.
结论:
- ASP3082是治疗KRAS(G12D) 突变癌症的一个有前途的候选药物.
- 基于结构的优化策略可以应用于其他近距离诱导药物.
- 目前ASP3082正在临床研究中.
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