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设计,合成和新型基于异印林的HPK1降解剂的药理学评估

Zhisheng Zhang¹, Xuan Zhang¹, Tizhi Wu¹

¹State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211100, PR China.

European journal of medicinal chemistry

|November 22, 2025

概括

研究人员开发了一种新型的PROTAC分子D02,该分子有效降解T细胞中的血液生成原生激酶1 (HPK1). 这种化合物通过促进T细胞反应,对免疫瘤疗法具有前景.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
生物化学生物化学

背景情况:

造血原体激酶1 (HPK1) 是T细胞信号传递的关键负调节剂.
对于免疫瘤学疗法来说,HPK1是一个具有挑战性但有吸引力的标.

研究的目的:

为HPK1降解设计和评估新型蛋白质分解向嵌合体 (PROTAC) 分子.
评估HPK1-向T细胞中的PROTACs的疗效和安全性.

主要方法:

针对HPK1的PROTAC的设计和合成.
在Jurkat细胞中评估HPK1降解和下游信号抑制.
在人类初级T细胞中评估IL-2和IFN-γ分泌.
初步的毒理学评估.

主要成果:

化合物D02显示出强烈的HPK1降解 (DC50=3.07±1.81nM,Dmax=98.33%) 的结果.
在Jurkat细胞中,D02抑制了SLP-76酸化 (IC50 = 11.38 nM).
D02在初级T细胞中强烈诱导IL-2和IFN-γ分泌 (EC50值分别为4.51nM和3.02nM).
在初步评估中,D02表现出了有利的安全概况.

结论:

化合物D02是一种强大的HPK1降解剂,具有显著的免疫调节作用.
D02代表了一个有希望的治疗候选人,用于进一步发展免疫瘤学.
向HPK1的PROTAC提供了一种新的策略来增强T细胞介导免疫力.

关键词:

编号:CRBN 编号:CRBN 编号:CRBN 编号:CRBN 编号:CRBN 编号:CRBN 编号:CRBN 降解器降解器降解器在HPK1中,HPK1是这就是PROTAC.

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