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计算和实验验证卡博桑提尼布的向DDX11以抑制肝癌中DNA损伤修复

Lianhai Li^1,2, Zhenhui Huang², Zhensen Liu²

¹Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.

|February 16, 2026

概括

用卡博桑提尼布等药物准DDX11在Ser237可以破坏肝癌中DNA损伤反应 (DDR) 信号传递. 这种方法有望通过降低DNA修复蛋白的调节来抑制癌症的进展.

科学领域:

生物化学生物化学
分子生物学分子生物学
在瘤学瘤学.

背景情况:

在Ser237中,阿塔克西亚特朗基切塔西亚突变 (ATM) 激酶酸化DDX11,激活肝癌中DNA损伤反应 (DDR).
向这个关键的酸化部位是抑制肝癌进展的潜在策略.

研究的目的:

通过计算药物重新定位方法,识别FDA批准的药物,能够针对DDX11的Ser237.
验证已识别的化合物在破坏肝癌细胞中ATM介导的DDR信号传递方面的有效性.

主要方法:

基于结构的,特定站点的对接对2367种药物进行了对DDX11残留物的选.
分子动力学模拟 (100 ns) 和MM-GBSA/MM-PBSA分析评估了结合的稳定性.
蛋白质基因分析评估了卡博桑提尼布对DNA修复蛋白和同源重组 (HR) 能力的影响.

主要成果:

七种候选药物显示出有利的结合亲缘关系;达科米替尼布,厄戈他和卡博桑提尼布与关键DDX11残留物表现出稳定的结合.
卡博桑提尼布显示与Ser237具有选择性相互作用,并优先进行验证.
卡博桑提尼布降低了肝癌细胞中的DNA修复蛋白和减弱HR修复能力.

结论:

将DDX11定位在Ser237上有效地抑制了ATM中介的DDR信号.
卡博桑提尼布通过抑制DNA修复途径,显示出作为肝癌治疗剂的潜力.
进一步的临床前和临床评估DDX11的向是必要的肝癌治疗.

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