发现一流的BAZ2A/B和BAZ2B选择性降解器
Leonardo Palaferri1, Iván Cheng-Sánchez1, Katherine Gosselé1,2
1Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
ACS medicinal chemistry letters
|February 19, 2025
概括
研究人员开发了新的蛋白质溶解向金马 (PROTACs),dBAZ2和dBAZ2B,以降解与指2A/2B (BAZ2A/B) 蛋白质相邻的odomain. 这些化合物为研究BAZ2A和BAZ2B在疾病中的不同作用提供了精确的工具.
科学领域:
- 生物化学 生物化学
- 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:
- 指2A和2B (BAZ2A/B) 邻的基原体是参与启动开关复合体的同类蛋白质.
- 尽管结构相似,BAZ2A/B可能在疾病发病过程中发挥不同的作用.
- 现有的抑制剂缺乏特异性,以类似的方式向BAZ2A和BAZ2B.
研究的目的:
- 发现和描述用于选择性降解BAZ2A/B蛋白质的新型化学探针.
- 开发一流的蛋白质溶解向金马 (PROTACs),向BAZ2A/B和BAZ2B.
主要方法:
- 设计和合成蛋白质溶解向嵌合体 (PROTACs).
- 使用DC50和Dmax值评估蛋白质降解功效.
- 在相关细胞系 (PC3,MM1S) 中评估降解动力学和持续时间.
主要成果:
- 发现了dBAZ2,这是一种降解BAZ2A/B的PROTAC (BAZ2A_DC50 = 180nM;BAZ2B_DC50 = 250nM).
- 发现了dBAZ2B,一个选择性降解BAZ2B的PROTAC (DC50 = 19 nM).
- 两种PROTAC在2小时内均达到97%以上的降解,在PC3和MM1S细胞中持续超过3天.
结论:
- dBAZ2和dBAZ2B分别是降解BAZ2A/B和BAZ2B蛋白质的有效第一级PROTAC.
- 这些化合物显示出高效率,选择性 (对于dBAZ2B),以及快速,持续的降解.
- dBAZ2和dBAZ2B作为有价值的化学探针,用于阐明BAZ2A/B在疾病中的独特生物功能.
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