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RLY-4008,第一个具有跨FGFR2变异和抗性突变活性的高选择性FGFR2抑制剂

Vivek Subbiah¹, Vaibhav Sahai², Dejan Maglic³

¹The University of Texas MD Anderson Cancer Center, Houston, Texas.

Cancer discovery

|June 4, 2023

概括

一种名为RLY-4008的新药显示出治疗纤维细胞生长因子受体2 (FGFR2) 癌症的前景. 这种选择性FGFR2抑制剂有效向癌症突变,同时避免使用更广泛的抑制剂所见的有毒副作用.

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:

瘤性纤维细胞生长因子受体2 (FGFR2) 激活驱动各种癌症,呈现出治疗点.
目前的泛FGFR抑制剂 (泛FGFRi) 显示出有效性,但受到FGFR1/FGFR4-介导毒性和获得的耐药性突变的限制.

研究的目的:

评估RLY-4008,一种新的,高度选择性的,不可逆转的FGFR2抑制剂,旨在克服现有疗法的局限性.
在临床前模型和早期临床试验中评估RLY-4008对初级FGFR2变异和抗性突变的疗效.

主要方法:

在体外评估RLY-4008对FGFR1和FGFR4的选择性,以及对FGFR2变化的活性.
在异种移植模型中对RLY-4008的体内评估,包括具有抗性突变的模型.
对治疗反应和异构毒性早期临床数据的分析.

主要成果:

在体外,RLY-4008表现出高选择性 (FGFR1的250倍,FGFR4的5000倍).
在异种移植模型中,RLY-4008诱导了瘤回归,包括具有抗性突变的模型,同时节省了FGFR1和FGFR4.
早期的临床试验显示反应没有显著的异构FGFR毒性.

结论:

RLY-4008是一种高度选择性的FGFR2抑制剂,对主要变异和耐药性突变有效.
选择性FGFR2抑制RLY-4008可以克服泛FGFRi的局限性,提供一种潜在的新疗法策略.
RLY-4008证明了FGFR2驱动癌症的广泛治疗潜力,并改善了安全性.

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