2. Academic Validation
  3. Discovery of 1,2,4-benzotriazine derivatives as new hematopoietic progenitor kinase 1 (HPK1) inhibitors

Discovery of 1,2,4-benzotriazine derivatives as new hematopoietic progenitor kinase 1 (HPK1) inhibitors

  • Bioorg Chem. 2025 Jan 10:156:108158. doi: 10.1016/j.bioorg.2025.108158.
Jie Mao 1,  Lixin Zhou 2,  Yuxing Wu 3,  Kaizhen Wang 1,  Xiuquan Ye 3,  Tianyu Wang 1,  Jiamei Yang 1,  Jun Tong 1,  Qi Miao 1,  Sheng Jiang 4,  Yibei Xiao 5,  Kuojun Zhang 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 3 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jiang_shengg@126.com.
  • 5 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yibei.xiao@cpu.edu.cn.
  • 6 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: kuojunzhang2017@163.com.
PMID: 39826501 DOI: 10.1016/j.bioorg.2025.108158
Abstract

Hematopoietic progenitor kinase 1 (HPK1), which negatively regulates immune signaling, has emerged as an attractive small-molecule drug target for tumor immunotherapy. Herein, we report the discovery of the 1,2,4-benzotriazine derivatives as new potent HPK1 inhibitors. Notably, compound A29 exhibited improved HPK1 inhibitory activity relative to compound 1 in the ADP-Glo kinase assay (IC50 = 2.70 and 13.6 nM, respectively). The pronounced inhibitory activity of A29 against downstream p-SLP76 in Jurkat T cells (IC50 = 8.1 nM) as well as the ability to induce the production of interleukin 2 (IL-2) in human peripheral blood mononuclear cells (PBMCs) confirmed its cellular target engagement and immune stimulatory effect. Consistently, this lead compound significantly enhanced T-cell killing ability against murine colon Cancer cells CT26 or MC38 in a co-culture system. Furthermore, A29 was efficacious in a CT26 xenograft mouse model alone, and significantly enhanced the antitumor efficacy of an anti-PD-1 antibody. This work provides a promising lead for the development of effective HPK1 inhibitors for tumor immunotherapy.

Keywords

Anti-tumor activity; HPK1; HPK1 inhibitor; Tumor immunotherapy.

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