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通过基于化学的直接对生物测试查和SAR优化发现新型HPK1抑制剂

Yiping Duan¹, Chen He¹, Zhichao Guo¹

¹Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, P. R. China.

Journal of medicinal chemistry

|March 13, 2026

概括

研究人员开发了一种结合化学和生物学的新方法,以寻找用于癌症免疫治疗的药物. 这种方法确定了一个强大的化合物,在临床前模型中显示出治疗瘤的前景.

科学领域:

药用化学医学化学
癌症免疫疗法免疫疗法
药物发现药物发现药物发现

背景情况:

造血原体激酶1 (HPK1) 是癌症免疫疗法的关键标,因为它在T细胞调节中的作用.
有效地探索新型HPK1抑制剂的化学空间对于的发现至关重要.

研究的目的:

开发一种综合的组合化学和生物测试方法,以加快识别HPK1抑制剂.
发现和优化针对HPK1进行癌症免疫治疗的新型化合物.

主要方法:

现有的HPK1抑制剂库的碎和再组合.
分子对接以识别首选的碎片.
基于微板的碎片组装和直接的生物测试.
结构-活动关系 (SAR) 研究用于优化.

主要成果:

通过基于碎片的组装和选来识别化合物8b.
优化导致化合物53具有强大的HPK1抑制活性 (IC50 = 1.7 nM).
化合物53证明了目标参与 (抑制SLP76酸化) 和功能作用 (增强IL-2释放).
化合物53在小鼠模型中表现出低CYP/hERG风险和强大的体内抗瘤功效.

结论:

综合组合化学-生物测定方法有效地加速了对HPK1.1等具有挑战性的目标的标识.
优化的化合物53显示出作为癌症免疫治疗的临床前候选人的巨大潜力.
开发的战略对于在药物发现计划中发现新疗法是有价值的.

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