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新型造血原始基因酶1抑制剂KHK-6增强T细胞激活

Min Jeong Ahn^1,2, Eun Hye Kim¹, Yunha Choi^1,3

¹Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.

|June 26, 2024

概括

一种新型化合物,KHK-6,有效地抑制造血原体基因酶1 (HPK1),增强T细胞激活和细胞因子生产,用于潜在的癌症免疫疗法.

科学领域:

免疫学免疫学免疫学
药理学药理学是指药理学的学科.
在瘤学瘤学.

背景情况:

抑制负免疫调节剂是免疫治疗的关键.
造血原体激酶1 (HPK1) 减弱T细胞激活,限制免疫反应.
HPK1是基于T细胞的癌症免疫疗法的可用药物标.

研究的目的:

设计和合成一种新的HPK1抑制剂,KHK-6.
评估KHK-6在抑制HPK1和增强T细胞激活方面的细胞活性.

主要方法:

设计和合成的KHK-6.
评估KHK-6对HPK1激酶活性和SLP-76酸化的抑制.
评估KHK-6对T细胞激活标记物和细胞因子产生的影响.
测试了KHK-6对T细胞中介杀死癌细胞的影响.

主要成果:

KHK-6 抑制了 HPK1 激酶活性 (IC50 = 20 nM).
在Ser-376.6上,KHK-6阻断了CD3/CD28诱导的SLP-76酸化.
KHK-6增强了细胞因子的产生和T细胞激活标志物 (CD69,CD25,HLA-DR).
KHK-6增加了T细胞介导的SKOV3和A549癌细胞的杀死.

结论:

KHK-6是一种新型ATP竞争型HPK1抑制剂.
KHK-6通过阻断HPK1下游信号来增强T细胞的功能激活.
KHK-6对抑制HPK1的癌症免疫疗法药物发现有希望.

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