作者: Meng, Linghua ; Xu, Shilin ; Sun, Jiaqi ; Wu, Feifei ; Li, Huiyu ; Li, Weiqiang ; Li, Jia ; Yu, Jinghua ; Sun, Yaoliang ; Xu, Lei ; An, Qi ; Diao, Xingxing ; Zhang, Laishun ; Zhang, Qian

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 (IC₅₀ 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.

2024-11-16·Future Medicinal Chemistry

An updated review of small-molecule HPK1 kinase inhibitors (2016-present)

Review

作者: Zhong, Wenyi ; Chen, Jichao ; Liu, Jie ; Xu, Shengtao ; Xu, Jinyi ; Guo, Zhichao ; Duan, Yiping

Hematopoietic progenitor kinase 1 (HPK1) is a serine-threonine kinase specific to hematopoiesis and a member of the MAP4K family of Ste20-related protein kinases. Targeting HPK1 to ameliorate T cell exhaustion and enhance T cell functions is a promising strategy for clinical immunotherapies. Numerous studies have reported the progress in developing effective HPK1 inhibitors and elucidating their mechanisms of action. However, most inhibitors affect multiple signaling pathways, resulting in unintended side effects that limit their clinical development and application. Herein, we reviewed HPK1-related signaling pathways, clinical candidates and recent advances in small-molecule inhibitors targeting HPK1. Additionally, we present our perspectives on current challenges and potential future research field, hoping to provide inspiration for the development of novel HPK1 inhibitors.

2022-04-17·Orvosi Hetilap4区 · 医学

Hátsószegmens-betegségek okozta látásromlás és vakság Magyarországon az 50 évnél idősebb korú lakosság körében

4区 · 医学

Article

作者: Németh, János ; Nagy, Zoltán Zsolt ; Sándor, Gábor László ; Szabó, Dorottya ; Tóth, Gábor ; Limburg, Hans

100 项与 HPK1抑制剂(AZ) 相关的药物交易

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