基于乙烯化的选择性希斯脱乙酶6 (HDAC6) PROTACs的开发
Daniel Stopper1, Irina Honin1, Felix Feller1
1Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
ACS medicinal chemistry letters
|March 19, 2025
概括
研究人员开发了用于HDAC6降解的新型蛋白质分解向嵌合体 (PROTACs),使用乙基化物作为基因毒性酸盐的更安全替代品. 化合物17c通过ubiquitin-proteasome系统显示出强有力的和选择性的HDAC6降解.
科学领域:
- 药用化学 医学化学
- 化学生物学 化学生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 基因组脱乙酶 (HDACs) 是药物发现的关键表观遗传标.
- 有针对性的蛋白质降解是一种有前途的治疗策略.
- 现有的HDAC抑制剂和降解剂通常使用基因毒性酸结合组.
研究的目的:
- 开发一种新的HDAC6向蛋白解向的仿真体 (PROTACs).
- 使用乙基化物部分作为一种非遗传毒性结合组 (ZBG).
- 为了实现HDAC6.6的强大和选择性降解.
主要方法:
- 综合CRBN和VHL招聘的PROTACs. 这是一个很好的例子.
- 使用各种测试评估HDAC6降解.
- 通过ubiquitin-proteasome系统进行降解机制的表征.
- 化学蛋白质组学来评估跨HDAC异型体的选择性.
主要成果:
- 确定了几种强大的HDAC6降解剂,降解率超过80%.
- 化合物17c显示HDAC6最大降解率为91%,DC50为14nM.
- 证实了通过无素-蛋白酶体系统进行降解.
- 化学蛋白质组学证实HDAC6对其他HDAC的选择性降解.
结论:
- 乙基化物作为HDAC降解剂的有效和更安全的ZBG替代品.
- 开发的PROTAC提供了一个有希望的方法,用于有针对性的HDAC6降解.
- 化合物17c是一种高效和选择性的HDAC6降解剂.
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