新的胺酸衍生物诱导了亡,并限制了白血病细胞的自
Marten A Fischer1, Al-Hassan M Mustafa2, Kristin Hausmann3
1Department of Toxicology, University Medical Center, 55131 Mainz, Germany.
Journal of advanced research
|July 19, 2023
概括
新型基因组脱乙酶抑制剂 (HDACi) 对I类HDACs,特别是HDAC3.3,表现出强烈的活性. 这些新的药物诱导了细胞亡,并调节了白血病细胞的自,确定了HDAC3作为一个有前途的癌症标.
科学领域:
- 表观遗传学和癌症生物学
- 药理学和药物发现
背景情况:
- 经过翻译后的蛋白质乙化,由基因素脱乙酶 (HDACs) 调节,对于生物过程至关重要.
- 失调的HDACs在瘤中很常见,导致开发HDAC抑制剂 (HDACi) 用于癌症治疗,特别是用于血液癌症.
研究的目的:
- 发现新型,强效和选择性I类HDAC抑制剂 (HDAC1-8) 与现有的药物相比具有更高的疗效.
- 阐明这些HDAC抑制剂调节癌细胞中亡和自之间的相互作用的机制.
主要方法:
- 新型胺-胺酸HDAC抑制剂的合成 (KH9,KH16,KH29).
- 在体外活动测试,分子建模和白血病细胞命运,乙化和蛋白质表达的分析.
- 利用DepMap数据库用于CRISPR-Cas9查数据,以确定人类白血病细胞的敏感性因素.
主要成果:
- 新型HDAC抑制剂对I类HDACs表现出纳米分子活性,其性能优于临床HDAC抑制剂SAHA.
- KH16 (yanostat) 显示出强烈的HDAC3抑制 (IC50 = 6 nM) 和强大的诱导白血病细胞的亡 (IC50 = 110 nM),同时节省正常细胞.
- 在115个人类血液癌细胞系中,HDAC3被确定为关键的依赖因子,无论p53突变如何. KH16调节了与亡相关的蛋白质,细胞循环和自标志物.
结论:
- 通过抑制白血病细胞的亡,HDACs对于稳定自蛋白至关重要.
- HDAC3代表了在癌症治疗中药理干预的验证治疗标.
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