发现一种共价抑制剂,选择性地向c-Src 激酶的自化部位
Huimin Zhang1,2, Dounan Xu1,2,3, Hongchan Huang4,5
1Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China.
ACS chemical biology
|March 21, 2024
概括
研究人员使用一种新的药物设计策略开发了一种选择性c-Src抑制剂, (R) -LW-Srci-8. 这种抑制剂针对独特的口袋和自酸化部位,显示出对c-Src的高强度和特异性.
科学领域:
- 药用化学 医学化学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 非受体氨酸激酶c-Src在细胞信号和癌症进展中至关重要.
- 由于其复杂的作用,开发选择性c-Src抑制剂是困难的.
- 之前的工作介绍了选择性激酶抑制剂的转化后修饰启发的药物设计 (PTMI-DD).
研究的目的:
- 设计和合成一种高度选择性的c-Src抑制剂.
- 调查该新型化合物的结合机制和抑制活性.
- 为了验证PTMI-DD战略开发向激酶抑制剂.
主要方法:
- 基于PTMI-DD的化合物的化学优化.
- 在体外生化测试 (IC50, kinact, K) 以评估功效和动力学.
- 结晶学以阐明结合相互作用.
- 在体外激酶分析和基于细胞活动的蛋白质分析 (ABPP).
主要成果:
- (R) -LW-Srci-8证明了对c-Src.的功效提高了75倍 (IC50 = 35.83 ± 7.21 nM).
- 结晶学数据揭示了关键的C-F··CO相互作用,有助于密切结合.
- (R) -LW-Srci-8在体外和细胞内选择性地抑制c-Src,优先结合非活性形式并破坏自化.
结论:
- 这项研究验证了PTMI-DD通过向独特的口袋和翻译后修改部位来创建选择性激酶抑制剂.
- 一种强效和选择性的c-Src抑制剂 (R) -LW-Srci-8得到开发.
- (R) -LW-Srci-8 作为一种有价值的化学探针,用于研究c-Src功能.
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