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发现INCB126503是一种强效和选择性的FGFR2/3抑制剂

Minh H Nguyen¹, Anlai Wang¹, Lisa Truong¹

¹Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States.

ACS medicinal chemistry letters

|June 18, 2025

概括

一种新药物INCB126503显示出作为向治疗由纤维细胞生长因子受体 (FGFR) 突变驱动的癌症的前景. 它有效地针对FGFR2/3,包括耐药形式,具有更好的选择性和减少副作用.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

异常的纤维细胞生长因子受体 (FGFR) 信号传递,特别是涉及FGFR2和FGFR3,是各种癌症的关键驱动因素,如胆管癌和泌尿腺癌.
目前针对FGFR2/3的治疗方法使用泛FGFR抑制剂,这些抑制剂可以通过抑制FGFR1/4引起非向毒性,并且易受获得性耐药性突变的影响.

研究的目的:

报告INCB126503的发现和临床前表征,这是一种新的,选择性抑制FGFR2和FGFR3.
在临床前癌症模型中评估INCB126503的疗效和安全性.

主要方法:

发现和描述INCB126503,评估其功效,同位体选择性和对守门员突变的活性.
在体内研究评估FGFR信号抑制,耐受性 (包括高酸血症) 和异种移植模型的抗瘤疗效与FGFR3变化.

主要成果:

INCB126503是一种强效,口服生物可用抑制剂,对FGFR2/3.3具有很高的选择性.
该化合物表现出对守门员突变物具有同实力的活性,克服了常见的抵抗机制.
在体内,INCB126503有效地抑制了FGFR信号传递,但没有导致过光血症.
在具有FGFR3基因变异的临床前模型中观察到显著的抗瘤疗效.

结论:

INCB126503是一种有前途的下一代FGFR2/3抑制剂,具有良好的选择性和安全性.
它克服耐药性和向特定FGFR变化的能力为改进癌症治疗策略提供了潜力.

关键词:

在FGFR的基础上.异形选择性是异形选择性的.基于结构的药物设计.结构 - 活动关系关系.异种移植模型异种移植模型

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