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硫法替尼与FGFR和CSF-1RR结合的结构基础和选择性

Qianmeng Lin^1,2, Shuyan Dai^1,2, Lingzhi Qu^1,2

¹Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

Communications chemistry

|January 3, 2024

概括

作为一种多位抑制剂的苏尔法丁尼布有效向FGFR1和CSF-1R. 它的结构机制揭示了克服耐药性和设计新型激酶抑制剂的洞察力.

科学领域:

分子生物学分子生物学
结构生物学是结构生物学.
药理学药理学是指药理学的学科.

背景情况:

获得的耐药性限制了单向激酶抑制剂.
像硫法替尼布这样的多位抑制剂提供了一种克服耐药性的策略.
苏尔法提尼布向FGFR1和CSF-1R,这与神经内分泌瘤有关.

研究的目的:

阐明硫法替尼与FGFR1和CSF-1R结合的分子机制.
了解硫法替尼的酶选择性的结构基础.
调查硫法替尼对FGFR和CSF-1R.中的守门员突变的敏感性.

主要方法:

用X射线结晶学测定硫法替尼与FGFR1和CSF-1R的结构.
生物化学测试以评估激酶抑制和对突变的敏感性.
结构分析以确定关键的约束相互作用和构造性适应性.

主要成果:

晶体结构揭示了硫法替尼对FGFR1和CSF-1R的共同结合特征和明显的构造适应性.
苏尔法丁尼布对特定的FGFR和CSF-1R守门员突变表现出敏感性.
对FGFR守门者突变的不敏感性与疏水性口袋相互作用有关,而旋转灵活性有助于CSF-1R抑制.

结论:

这项研究提供了对硫法提尼布抑制FGFR1和CSF-1R的结构性理解.
这些发现强调了疏水性相互作用对FGFR选择性的重要性.
洞察力指导了多位FGFR抑制剂的合理设计,具有更好的选择性和耐药性.

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