2. Academic Validation
  3. Design, synthesis, and biological evaluation of 2,4-diaminopyrimidine inhibitors of hematopoietic progenitor kinase 1

Design, synthesis, and biological evaluation of 2,4-diaminopyrimidine inhibitors of hematopoietic progenitor kinase 1

  • Bioorg Med Chem Lett. 2025 Aug 1:123:130242. doi: 10.1016/j.bmcl.2025.130242.
Chunting Li 1,  Jiuyu Liu 2,  Le Ren 1,  Long Zhang 1,  Na Zhang 1,  Shaoxuan Yan 1,  Yu Wang 1,  Siyu Fu 1,  Jiakuan Wei 1,  Hao Yue 1,  Yongshuo Wu 1,  Minghui Tong 3,  Xuan Shi 3,  Han Wang 3,  Dong Zhao 4,  Qingfeng Shao 4,  Yuanle Zhang 4,  Yanfang Zhao 1,  Yunlei Hou 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China.
  • 2 Department of Biomedical and Chemical Engineering, Liaoning Institute of Science and Technolgy, Benxi 117004, China. Electronic address: jiuyuliu102194@163.com.
  • 3 3D BioOptima, 1338 Wuzhong Avenue, Suzhou 215104, China.
  • 4 Yangtze River Pharmaceutical Group Jiangsu Haici Biological Pharmaceutical Co., Ltd., No. 8 Taizhen Road, Medical New & Hi-tech Industrial Development Zone, Taizhou City, Jiangsu Province, China.
  • 5 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China.. Electronic address: houyunlei901202@163.com.
PMID: 40246181 DOI: 10.1016/j.bmcl.2025.130242
Abstract

Cancer Immunotherapy is an emerging anti-cancer strategy that enhances immune circulation by targeting the immune system. Among the various targets, HPK1, a member of the mammalian Ste20-like protein serine/threonine kinase family, serves as a crucial negative regulator of immune-mediated mechanisms, positioning it as a promising target for immunotherapy. Herein, based on the reported HPK1 inhibitors characterized by 2,4-diaminopyrimidine components, four series of derivatives were obtained through structural optimization methods. Compound 10c demonstrates significant inhibitory effects on HPK1 kinase, with an IC50 of 0.09 nM. Additionally, it markedly inhibits the phosphorylation of the downstream adaptor protein SLP76, with an IC50 of 33.74 nM, and effectively stimulates the secretion of the T cell activation marker IL-2, exhibiting an EC50 of 84.24 nM. These findings suggest that compound 10c holds considerable promise for applications in immunotherapy.

Keywords

2,4-diaminopyrimidine; HPK1; Immune checkpoint inhibitors; Tumor immunotherapy.

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