Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
Bioorg Chem. 2023 Nov;140:106811. doi: 10.1016/j.bioorg.2023.106811. Epub 2023 Aug 26.
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 IC 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，但其中等的反应率限制了其广泛应用。造血祖细胞激酶 1（HPK1）作为 T 细胞受体的重要负调节剂，已被确定为增强抗肿瘤免疫的有前途的靶点。然而，开发选择性 HPK1 抑制剂仍然具有挑战性。在此，我们通过基于结构的合理设计，报道了一系列新型 1H-吡唑并[3,4-d]嘧啶衍生物作为 HPK1 抑制剂。最佳化合物 10n 对 HPK1 的抑制作用显著，IC 值为 29.0 nM，对 SLP76 的磷酸化作用在低至 0.1 μM 的浓度下即可实现。此外，化合物 10n 在包括同 MAP4K 家族的 GLK 在内的 25 种激酶的筛选中表现出良好的选择性。综上所述，本研究提供了一种新型、有效且选择性的 HPK1 抑制剂，可作为癌症免疫治疗的先导化合物。
