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  3. Discovery of novel and potent 2-aminopyrazine-based HPK1 inhibitors enhancing T-cell immunity against cancer

Discovery of novel and potent 2-aminopyrazine-based HPK1 inhibitors enhancing T-cell immunity against cancer

  • Eur J Med Chem. 2026 Apr 15:308:118689. doi: 10.1016/j.ejmech.2026.118689.
Zhichao Guo 1,  Yiping Duan 1,  Baixue Zhang 1,  Kai Sun 1,  Tiandong Zheng 1,  Lanlan Chen 2,  Chen He 1,  Jiajie Feng 1,  Yang Lu 2,  Geting Xiong 2,  Shengtao Xu 3,  Jie Liu 4,  Zheying Zhu 5,  Jinyi Xu 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China.
  • 2 Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China. Electronic address: cpuxst@163.com.
  • 4 Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China. Electronic address: cpu-jill@163.com.
  • 5 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, Nottingham, NG7 2RD, UK.
  • 6 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China. Electronic address: jinyixu@china.com.
PMID: 41747509 DOI: 10.1016/j.ejmech.2026.118689
Abstract

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for immuno-oncology. Although numerous campaigns have been conducted to identify potent and selective HPK1 inhibitors, few encouraging clinical outcomes have been reported. Herein, we present the optimization of 2E, an HPK1 inhibitor with a new 2-aminopyrazine scaffold. It was identified through a fragment-based deconstruction-reconstruction (FBDR) strategy. This process led to the discovery of a novel and highly potent HPK1 inhibitor 39, possessing nanomolar potency in biochemical and cellular assays. Mechanistic studies revealed that 39 effectively enhanced IL-2 cytokine production and counteracted prostaglandin E2 (PGE2)-mediated immunosuppression in Jurkat cells. Crucially, compound 39 showed T-cell-dependent antitumor efficacy in the CT26-Balb/c syngeneic tumor model and exhibited significant synergistic effects when combined with anti-PD-1 in vivo. Moreover, compound 39 enhanced infiltration of CD3+/CD8+ T cells into tumor tissues, verifying its immune-mediated antitumor mechanisms. These findings highlight compound 39 as a promising candidate for Cancer Immunotherapy, deserving further optimization and preclinical research.

Keywords

2-Aminopyrazine; Anti-tumor mechanisms; Cancer immunotherapy; HPK1; Small-molecule kinase inhibitors.

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