Despite immune checkpoint inhibitors' tremendous success in the treatment of tumors, the moderate response rate limits their widespread use. Hematopoietic progenitor kinase 1 (HPK1) is served as an essential negative regulator of T-cell receptor, which has been identified as a promising target for enhancing antitumor immunity. However, the development of a selective HPK1 inhibitor is still challenging. Herein, we reported a novel series of 1H-pyrazolo[3,4-d]pyrimidine derivatives as HPK1 inhibitors by structure-based rational design. The optimal compound 10n significantly inhibited HPK1 with an IC₅₀ value of 29.0 nM and the phosphorylation of SLP76 at a concentration as low as 0.1 μM. Furthermore, compound 10n exhibited good selectivity over a panel of 25 kinases, including GLK from the same MAP4K family. Together, the current study provided a novel, potent, and selective HPK1 inhibitor, acting as a lead compound for the future development of cancer immunotherapy.

尽管免疫检查点抑制剂在肿瘤治疗方面取得了巨大成功，但其缓慢的反应率限制了其广泛使用。造血祖细胞激酶 1 (HPK1) 是 T 细胞受体的重要负调节因子，已被确定为增强抗肿瘤免疫的有希望的靶点。然而，选择性 HPK1 抑制剂的开发仍然具有挑战性。在此，我们通过基于结构的合理设计报道了一系列新型 1 H -吡唑并[3,4- d ]嘧啶衍生物作为 HPK1 抑制剂。最佳化合物10n在低至0.1 μM的浓度下即可显着抑制HPK1（IC ₅₀值为29.0 nM）和SLP76的磷酸化。此外，化合物10n对 25 种激酶（包括来自同一 MAP4K 家族的 GLK）表现出良好的选择性。总之，当前的研究提供了一种新型、有效的、选择性的 HPK1 抑制剂，可作为癌症免疫疗法未来发展的先导化合物。