Wu Feifei, Li Huiyu, Li Weiqiang, Zhang Laishun, An Qi, Sun Jiaqi, Zhang Qian, Sun Yaoliang, Xu Lei, Yu Jinghua, Diao Xingxing, Li Jia, Meng Linghua, Xu Shilin
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, #555 Zu Chong Zhi Road, Shanghai 201203 China; University of Chinese Academy of Sciences, Beijing 100049, China.
Division of Anti-Tumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203 China; University of Chinese Academy of Sciences, Beijing 100049, China.
Bioorg Med Chem. 2025 Mar 1;119:118079. doi: 10.1016/j.bmc.2025.118079. Epub 2025 Jan 21.
Hematopoietic progenitor kinase 1 (HPK1) has emerged as a promising target for cancer immunotherapy due to its critical role as a negative regulator of T cell receptor (TCR) signaling. Despite this potential, no HPK1 inhibitors have been approved for cancer treatment, underscoring the need for structurally novel inhibitors. Herein, we describe the design, synthesis and biological evaluation of a series of potent HPK1 inhibitors based on our previously identified hit 9. Among them, compound 24 demonstrated strong HPK1 inhibition (IC of 10.1 nM) and effectively suppressed phosphorylation of the downstream protein SLP76. Notably, compound 24 exhibited enhanced potency in promoting IL-2 secretion in Jurkat T cells, reduced cellular toxicity, and improved liver microsomal stability compared to hit 9. Overall, this study provides a promising lead compound for further optimization as a candidate for cancer immunotherapy.
造血祖细胞激酶1（HPK1）已成为癌症免疫治疗的一个有前景的靶点，因为它作为T细胞受体（TCR）信号的负调节因子发挥着关键作用。尽管有这种潜力，但尚无HPK1抑制剂被批准用于癌症治疗，这突出了对结构新颖的抑制剂的需求。在此，我们描述了基于我们之前鉴定的先导化合物9设计、合成和生物学评价的一系列有效的HPK1抑制剂。其中，化合物24表现出强烈的HPK1抑制作用（IC为10.1 nM），并有效抑制下游蛋白SLP76的磷酸化。值得注意的是，与先导化合物9相比，化合物24在促进Jurkat T细胞中IL-2分泌方面表现出增强的效力，降低了细胞毒性，并提高了肝微粒体稳定性。总体而言，本研究为作为癌症免疫治疗候选药物的进一步优化提供了一个有前景的先导化合物。
