Discovery of a Novel Potent and Orally Efficacious PROTAC Degrader of HPK1 for Tumor Immunotherapy

作者：Jun Tong, Kaizhen Wang, Chenyi Liu, Lin Wang, Qi Miao, Yuxing Wu, Zhiyi Zhang, Zepeng Liao, Sheng Jiang, Ruo Wang, Yibei Xiao, Kuojun Zhang · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00970 · 被引用次数：6 · 研究领域：Protein Degradation and Inhibitors、Peptidase Inhibition and Analysis、CAR-T cell therapy research

Abstract Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of the TCR signaling pathway, has emerged as an attractive drug target for tumor immunotherapy. Herein, we report the discovery of a series of pyrazine-based HPK1 PROTAC degraders. The representative compound 10m demonstrated potent and sustained HPK1 degradation (DC50 = 5.0 ± 0.9 nM; Dmax ≥ 99%). Upon TCR activation, 10m significantly inhibited SLP76 phosphorylation and enhanced ERK pathway activation through degrading HPK1, thereby stimulating IL-2 and IFN-γ release. Furthermore, 10m exhibited the ability to overcome the immunosuppressive effects imposed by PGE2, NECA or TGF-β. Notably, orally administration of 10m alone efficaciously inhibited tumor growth in an MC38 syngeneic mouse model. Moreover, 10m achieved a superior antitumor effect when combined with PD-1 blockade, suggesting the complementarity between the two treatment modalities. Overall, this work provides promising lead compounds for the clinical development of HPK1 PROTACs as small-molecule therapeutics in tumor immunotherapy.