单选择性素脱乙酶6 PROTAC降解剂 在体外显示可追溯性
Harsimran K Garcha1,2, Olasunkanmi O Olaoye1,2, Abootaleb Sedighi1
1Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
Journal of medicinal chemistry
|March 10, 2025
概括
我们开发了TO-1187,一种新型的蛋白质分解向化体 (PROTAC),可以在细胞和体内选择性降解HDAC6. 这种强效的分子显示出进一步研究HDAC6生物学和潜在的治疗应用的前景.
科学领域:
- 化学生物学 化学生物学
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 海斯脱乙酶6 (HDAC6) 涉及各种细胞过程和疾病.
- 使用向蛋白质溶解的嵌合体 (PROTACs) 进行向蛋白质降解是一种新兴的治疗策略.
研究的目的:
- 设计和描述一种新的PROTAC,TO-1187,用于选择性降解HDAC6.6.
- 评估TO-1187.7的体外和体内疗效和选择性.
主要方法:
- 通过将HDAC6抑制剂 (TO-317) 与大脑细胞 (CRBN) 连接物 (波马利多米德) 连接PROTAC设计.
- 在人体多发性骨髓瘤细胞 (MM.1S) 中HDAC6降解的体外评估.
- 蛋白质组分析以确定全蛋白质组降解概况和选择性.
- 在小鼠组织中对HDAC6降解的体内评估.
主要成果:
- 在MM.1S细胞中,TO-1187实现了强大的和单选择性的HDAC6降解 (DC50 = 5.81 nM).
- 没有观察到其他HDAC或已知的CRBN新基质的降解,直到25μM.
- 蛋白质基因分析证实了高选择性,只有HDAC6减少.
- TO-1187在注射后在小鼠组织中表现出高效的体内HDAC6降解.
结论:
- TO-1187是一种强效和选择性HDAC6向的PROTAC,在体外和体内已证明有效性.
- 该化合物具有有利的选择性,避免了其他HDAC和CRBN新基质的降解.
- TO-1187是进一步临床前开发和研究HDAC6生物学的一个有希望的候选人.
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