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开发一种RIPK1降解剂,以增强抗瘤免疫力

Xin Yu^1,2, Dong Lu³, Xiaoli Qi^1,2

¹The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.

Nature communications

|December 16, 2024

概括

我们开发了LD4172,一种新的PROTAC降解剂,准受体相互作用蛋白激酶1 (RIPK1). 这种RIPK1降解剂通过触发细胞死亡和改善抗瘤免疫反应来增强癌症免疫疗法.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
分子生物学分子生物学

背景情况:

受体相互作用蛋白激酶1 (RIPK1) 在癌症抵抗免疫检查点阻塞 (ICB) 中起着至关重要的作用.
准RIPK1是增强癌症免疫疗法的有希望的策略.
由于其定义不佳的绑定口袋,RIPK1的中间域提出了挑战.

研究的目的:

开发一种新的RIPK1降解剂,使用蛋白质溶解向嵌合体 (PROTAC) 技术.
研究RIPK1降解在克服对ICBs的耐药性的治疗潜力.

主要方法:

利用PROTAC技术设计和合成一种被指定为LD4172.2的RIPK1降解剂.
在体外和体内评估LD4172对RIPK1降解的效力和选择性.
在小鼠模型中评估LD4172对癌细胞死亡,免疫细胞反应和瘤对抗PD1治疗的敏感性的影响.

主要成果:

LD4172在体外和体内都显示出强大且有选择性的RIPK1降解.
通过LD4172降解RIPK1,诱导免疫细胞死亡.
在小鼠中,LD4172治疗增强了瘤透淋巴细胞的反应,并使瘤对抗PD1疗法的敏感.

结论:

LD4172是一种有效的RIPK1降解剂,在癌症免疫治疗中具有潜在的治疗应用.
这种RIPK1降解剂可以作为一个有价值的化学探针来研究RIPK1的脚手架功能.
针对RIPK1降解提供了一种策略,以改善患者对ICB的反应.

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