Chen Long, Zhang Baixue, Zhou Pijun, Duan Yiping, He Chen, Zhong Wenyi, Wang Tianyi, Xu Shengtao, Chen Jichao, Yao Hong, Xu Jinyi
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
Bioorg Chem. 2024 Dec;153:107814. doi: 10.1016/j.bioorg.2024.107814. Epub 2024 Sep 12.
Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T cell receptor signaling, plays a crucial role in multiple cellular immune responses. Emerging researches have demonstrated that inhibiting HPK1 kinase function enhances T cells' ability to recognize tumor antigens and boosts anti-tumor immune responses. As a result, HPK1 has become a promising target for tumor immunotherapy. Herein, we report the design, synthesis, and biological evaluation of a series of novel HPK1 inhibitors featuring a 3-cyano-quinoline scaffold. Among these, compound 3a was identified as the most potent HPK1 inhibitor (HPK1 IC = 48 nM). It effectively inhibited SLP76 phosphorylation, enhanced IL-2 cytokine secretion, and reversed PGE2-induced immunosuppression in Jurkat cells. In addition, compound 3a exhibited favorable metabolic stability in mouse liver microsomes and plasma. Overall, this work provides a structurally novel lead compound for the development of HPK1 inhibitors.
造血祖细胞激酶1（HPK1）是T细胞受体信号传导的负调节因子，在多种细胞免疫反应中起关键作用。新出现的研究表明，抑制HPK1激酶功能可增强T细胞识别肿瘤抗原的能力，并增强抗肿瘤免疫反应。因此，HPK1已成为肿瘤免疫治疗的一个有前景靶标。在此，我们报告了一系列以3-氰基喹啉骨架为特征的新型HPK1抑制剂的设计、合成及生物学评价。其中，化合物3a被确定为最有效的HPK1抑制剂（HPK1 IC = 48 nM）。它有效抑制了Jurkat细胞中SLP76的磷酸化，增强了IL-2细胞因子的分泌，并逆转了PGE2诱导的免疫抑制。此外，化合物3a在小鼠肝微粒体和血浆中表现出良好的代谢稳定性。总体而言，这项工作为HPK1抑制剂的开发提供了一种结构新颖的先导化合物。
