Xu Jiamei, Li Yingzhou, Chen Xinyi, Yang Junyi, Xia Heye, Huang Wenhai, Zeng Shenxin
School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China.
School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China.
Bioorg Chem. 2024 Dec;153:107866. doi: 10.1016/j.bioorg.2024.107866. Epub 2024 Oct 4.
Hematopoietic Progenitor Kinase 1 (HPK1, also known as MAP4K1) is a hematopoiesis-specific serine/threonine kinase that belongs to the MAP4K family of Ste20-related protein kinases. HPK1 has been identified as a negative regulator of T-cell receptor signaling. Recent studies have indicated that the inhibition or knockout of HPK1 kinase function can effectively alleviate T cell exhaustion, enhance T cell functionality, and improve the therapeutic efficacy of tumor immunotherapy. In recent years, small molecule chemical drugs targeting HPK1 have made significant progress and have become a hot topic in the research and development of tumor immunotherapy drugs. However, the advancement of small molecule drugs that target HPK1 is hindered by various challenges, including the limited selectivity, insufficient immune stimulation, and the ambiguity surrounding role of non-kinase scaffold functions of HPK1 in tumor immune responses. This review briefly describes the biological structure of HPK1 and its related signaling pathways in tumor immunity, systematically discusses the latest research progress in small molecule chemical drugs targeting HPK1. Finally, we summarize and prospect the opportunities and challenges in the drug development of small molecule chemical drugs targeting HPK1 in tumor immunity.
造血祖细胞激酶1（HPK1，也称为MAP4K1）是一种造血特异性丝氨酸/苏氨酸激酶，属于Ste20相关蛋白激酶的MAP4K家族。HPK1已被确定为T细胞受体信号传导的负调节因子。最近的研究表明，抑制或敲除HPK1激酶功能可有效缓解T细胞耗竭，增强T细胞功能，并提高肿瘤免疫治疗的疗效。近年来，靶向HPK1的小分子化学药物取得了重大进展，已成为肿瘤免疫治疗药物研发的热点话题。然而，靶向HPK1的小分子药物的进展受到各种挑战的阻碍，包括选择性有限、免疫刺激不足以及HPK1的非激酶支架功能在肿瘤免疫反应中的作用尚不明确。本文简要描述了HPK1的生物学结构及其在肿瘤免疫中的相关信号通路，系统地讨论了靶向HPK1的小分子化学药物的最新研究进展。最后，我们总结并展望了靶向HPK1的小分子化学药物在肿瘤免疫药物开发中的机遇与挑战。
