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开发VER-50589类似物作为新型Hsp90抑制剂

Xixi Fang¹, Jinhong Feng², Kewei Wang³

¹Department of Medicinal Chemistry, School of Pharmacy, Qingdao University Medical College, Qingdao University, Qingdao, Shandong, China; Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao University, Qingdao, Shandong, China.

Bioorganic & medicinal chemistry letters

|June 14, 2023

概括

研究人员设计了一种新型化合物,12-1,它强烈抑制热冲击蛋白90 (Hsp90) 并抑制瘤细胞的生长,为癌症治疗提供了一个有前途的新途径.

科学领域:

在瘤学瘤学.
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:

热冲击蛋白90 (Hsp90) 是一个关键的分子伴侣,也是癌症治疗中验证的标.
现有的Hsp90抑制剂,如VER-50589和Geldanamycin显示治疗潜力,但有局限性.

研究的目的:

合理设计和合成基于VER-50589.9结构的新型Hsp90抑制剂.
评估设计化合物的抗癌疗效和作用机制.

主要方法:

基于结构的药物设计和模拟合成.
在体外测试以确定Hsp90抑制活性 (IC50).
瘤细胞增殖,细胞亡和细胞周期分析.
西方斑点用于评估Hsp90客户端蛋白质水平.
分子动力学模拟.分子动力学模拟.

主要成果:

化合物12-1显示出强大的Hsp90抑制,IC50为9nM.
12-1有效抑制了6个人类瘤细胞系 (纳米IC50值) 的增殖,表现优于VER-50589和Geldanamycin.
12-1诱导瘤细胞亡和G0/G1细胞周期停止.
观察到Hsp90客户端蛋白CDK4和HER2的下调.
分子动力学模拟证实了12-1对Hsp90的N端ATP结合部位的有利结合.

结论:

化合物12-1是一种强效的Hsp90抑制剂,具有显著的抗癌活性.
12-1通过诱导亡,细胞循环停止和降低关键客户端蛋白质来发挥其作用.
良好的结合相互作用表明12-1是癌症治疗进一步发展的有希望的候选人.

关键词:

这是一种抗瘤药物.停靠的对接方式在Hsp90中,它是Hsp90的.抑制剂的抑制剂这里是 VER-50589 的位置.

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