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通过虚拟查和分子动力学模拟发现和描述新型FGFR1 V561M抑制剂

Yang Lu¹, Bizhi Li², Xiaoli Zheng¹

¹Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China.

ACS medicinal chemistry letters

|August 20, 2025

概括

一种新型化合物,1457983-28-6,有效抑制FGFR1 V561M突变,提供了一个有前途的新疗法. 这一发现解决了对FGFR1抑制剂耐药性的第二代治疗的迫切需要.

科学领域:

癌症学
药理学
计算化学

背景情况:

纤维细胞生长因子受体1 (FGFR1) 突变,特别是V561M,对现有的FGFR1抑制剂产生耐药性.
这种耐药性需要开发新的向疗法来维持治疗效果.

研究的目的:

识别和描述对FGFR1 V561M耐药突变有效的新化合物.
探索克服FGFR1抑制剂耐药性的潜在治疗策略.

主要方法:

采用了结合基于能源的选和机器学习的虚拟选协议.
用同质时间解析光 (HTRF) 生物测试来评估抑制活性.
基于细胞的测试 (Huh-7细胞系) 评估了生长抑制和克隆形成.
进行了分子动力学模拟以阐明结合相互作用.

主要成果:

鉴定出一种新型化合物1457983-28- 6, 具有对FGFR1 V561M (IC50=90. 24nM) 的强烈抑制作用.
化合物1457983-28-6显著抑制了Huh-7细胞生长和克隆形成.
分子动力学模拟显示了关键的结合相互作用,突出了Lys514的作用.

结论:

化合物1457983-28-6是第二代FGFR1抑制剂的一个有希望的候选物.
针对Lys514残留物提供了克服V561M介导耐药性的潜在策略.
这项研究为开发具有抗性突变的FGFR1驱动癌症的新疗法提供了基础.

关键词:

其他:机器学习分子动态突变虚拟选

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