基于DCAF16的共价降解手柄用于降解器的模块化设计
Lauren M Orr1,2,3, Sydney J Tomlinson4,5,3, Hannah R Grupe1,2,3
1Department of Chemistry. University of California, Berkeley, Berkeley, California 94720, United States.
ACS central science
|July 29, 2025
概括
研究人员开发了一种新型的共价降解柄,可实现向蛋白质降解. 这种通用的手柄可以应用于各种联结体,促进治疗开发的BRD4和雄激素受体 (AR) 等具有挑战性的标的降解.
科学领域:
- 化学生物学 化学生物学
- 药物发现 药物发现 药物发现
- 分子生物学分子生物学
背景情况:
- 有针对性的蛋白质降解是一种有前途的治疗策略.
- 设计有效的单价或分子降解剂是复杂的.
研究的目的:
- 为了确定针对蛋白质降解的新型共价降解柄.
- 在降解剂设计中探索E3酶相互作用.
主要方法:
- 合成BET-域抑制剂JQ1类似物与电友的手柄.
- 用于评估目标蛋白质的蛋白酶依赖性降解的测试.
- 识别E3结合酶合作伙伴和共价变异部位.
主要成果:
- 一个精细的烟胺手柄通过CUL4DCAF16.16诱导了蛋白酶体依赖的BRD4降解.
- 一个截断的烟胺手柄显示了更广泛的基质范围,降解BRD4,CDK4/6,SMARCA2/4和AR/AR-V7.
- 截断的手柄针对CUL4DCAF16在C173和C178.8的位置.
结论:
- 确定了一种针对DCAF16的新型共价降解柄.
- 这个手柄可以在各种向蛋白质的连接体中移植.
- 允许单价或双功能降解剂的模块化设计,用于具有挑战性的目标.
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