发现了新的基因醇分子作为p97/VCP抑制剂
Xiaoyi Zhang1,2, Lingna Jiang1,2, Yixin Li1,2
1Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, Beijing, China.
Frontiers in pharmacology
|June 30, 2023
概括
新的DBeQ类似物被开发为潜在的p97抑制剂. 化合物6显示出显著的抗瘤作用和高安全性,改善了p97抑制剂的临床潜力.
科学领域:
- 生物化学 生物化学
- 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:
- 蛋白p97是一种AAA ATPase,对于细胞过程如细胞周期控制,自和NF-κB激活至关重要.
- 由于p97的失调与各种疾病有关,因此它成为治疗干预的目标.
研究的目的:
- 设计,合成和评估新的DBeQ类似物作为蛋白质p97.7的潜在抑制剂.
- 评估这些新型化合物的体外和体内疗效和安全性.
主要方法:
- 合成了八种新的DBeQ类似物.
- 在体外p97ATPase抑制试验.
- 使用癌细胞系 (HCT116,RPMI-8226,s180) 和正常人结肠细胞系进行细胞增殖测定.
- 西部斑点分析以确认p97通路的抑制.
- 使用s180异种移植小鼠模型进行体内研究.
主要成果:
- 化合物6和7表现出强大的p97 ATPase抑制,超过已知的抑制剂.
- 化合物4-7诱导癌细胞的细胞循环停止,而化合物4-6显示出强大的抗增殖作用.
- 化合物4-6对癌细胞具有选择性细胞毒性,对正常细胞毒性较低.
- 在体内研究表明,化合物6抑制了瘤生长,并降低了p97水平,没有显著的毒性,可能避免骨髓抑制.
结论:
- 化合物6和7是有希望的p97抑制剂,可降低细胞毒性.
- 化合物6表现出强烈的抗瘤活性,良好的安全性概况和对p97的高结合亲和力,增强了其临床潜力.
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