高通量联体多样化,以发现近距离的化学诱导剂
James B Shaum1, Miquel Muñoz I Ordoño2,3, Erica A Steen1
1Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Nature chemical biology
|February 16, 2026
概括
研究人员开发了一种新的高通量化学 (HTC) 方法来发现近距离的化学诱导剂 (CIP). 这种方法成功地发现了ENL和BRD4蛋白质的新型降解剂,推进了近距离药理学.
科学领域:
- 生物化学 生物化学
- 化学生物学 化学生物学
- 分子药理学分子药理学
背景情况:
- 接近的化学诱导剂 (CIPs) 稳定生物分子相互作用,使细胞生物化学重新连接.
- 理性设计加快了异构生物功能CIP的发现,但分子的识别通常依赖于偶然性.
研究的目的:
- 系统地发现新的CIP,用各种化学修饰来装饰现有的配体.
- 探索高通量化学 (HTC) 的潜力,以识别新的分子和蛋白质降解剂.
主要方法:
- 采用基于硫化物交换的HTC在ENL和BRD4配体上安装了3,163个构建块.
- 对降解活性进行选,以确定新型CIP.
- 描述了已识别的化合物的相互作用接口和E3酶招募机制.
主要成果:
- 发现了dHTC1,一种ENL降解剂,通过扩展的蛋白质-蛋白质相互作用接口招募CRL4.
- 确定了dHTC3,一种分子,可选择性地使BRD4基1与SCFFBXO3二元化.
- 证明HTC是发现新型CIP和近距离药理学效应物的有效策略.
结论:
- 高通量化学 (HTC) 为发现近距离化学诱导剂 (CIP) 提供了一种简单而系统的方法.
- 这种方法扩大了针对蛋白质降解的可访问的E3链酶的目录.
- 已识别的化合物dHTC1和dHTC3代表了近距离药理学和药物发现的新工具.
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