隐藏在眼前:优化拓酶IIα抑制剂到Hsp90β选择性结合剂
Jaka Dernovšek1, Tjaša Goričan2, Marius Gedgaudas3
1Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
European journal of medicinal chemistry
|October 10, 2024
概括
开发异形选择性Hsp90抑制剂可以规避抗癌药物开发中常见的热冲击反应 (HSR). 针对细菌DNA旋转酶B和人类拓聚酶IIα的重定位抑制剂显示出选择性Hsp90抑制的前景.
科学领域:
- 生物化学 生物化学
- 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) 伴侣对于稳定致癌蛋白质至关重要,使他们成为癌症治疗的目标.
- 现有的Hsp90抑制剂通常由于诱导热冲击反应 (HSR) 而失败,从而限制了它们的临床效用.
- 开发异形选择性Hsp90抑制剂是克服HSR和提高治疗疗效的战略.
研究的目的:
- 重新利用细菌DNA旋转酶B和人类拓聚酶IIα的ATP竞争性抑制剂来抑制Hsp90.
- 识别具有针对特定异型的选择性新型Hsp90抑制剂,特别是Hsp90β超过Hsp90α.
- 评估选择性Hsp90抑制剂的抗癌潜力和安全性.
主要方法:
- 对内部抑制剂库进行针对Hsp90.0.的虚拟选.
- 生物化学测试以评估Hsp90结合亲和力和异型选择性.
- 在体外癌症细胞系生长抑制试验.
- 对Hsp90客户端蛋白水平和细胞周期进展的分析.
- 在斑马鱼幼虫中进行毒理学研究.
- 分子建模和STDNMR研究以阐明选择性机制.
主要成果:
- 化合物11对Hsp90具有较低的微分子亲和力,对Hsp90β比Hsp90α具有12倍的选择性.
- 在29种类型中,16种类型表现出Hsp90β偏好.
- 在实验室中,11种化合物抑制了癌细胞的生长.
- 化合物24e表现出Hsp90β选择性 (≥27倍),降低了Hsp90客户端蛋白,在没有HSR的情况下诱导了G0/G1细胞循环停止,并表现出对拓酶IIα和激酶的选择性.
- 化合物24e在斑马鱼幼虫中无毒.
- 分子建模和STD NMR证实,在Hsp90α中的S52A处的Serine到Alanine切换驱动着异形选择性.
结论:
- 针对细菌DNA旋转酶B和人类拓聚酶IIα的重定位抑制剂可以成为有效的Hsp90抑制剂.
- 化合物24e是一种强效和选择性的Hsp90β抑制剂,具有有前途的抗癌活性和有利的安全性.
- S52A突变是实现Hsp90α和Hsp90β异型之间选择性的关键,为未来的药物开发提供了合理的设计策略.
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