2. Academic Validation
  3. Discovery of the first dual PD-L1/JAK inhibitor with enhanced in vivo antitumor immunity

Discovery of the first dual PD-L1/JAK inhibitor with enhanced in vivo antitumor immunity

  • Eur J Med Chem. 2026 Mar 15:306:118605. doi: 10.1016/j.ejmech.2026.118605.
Zhijie Wang 1,  HaiQi He 2,  Jianwei Xu 2,  Xiaotong Liao 2,  Jun Tan 2,  Chenglong Xu 2,  Jiamin Tan 2,  Lirong Zhang 2,  Qin Wang 2,  Xixiang Yang 2,  Yichang Ren 2,  Guangfa Wang 3,  Yanle Zhi 4,  Jianjun Chen 5
Affiliations

Affiliations

  • 1 Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
  • 4 Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China. Electronic address: [email protected].
  • 5 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
PMID: 41581364 DOI: 10.1016/j.ejmech.2026.118605
Abstract

Programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors are widely recognized as an effective therapeutic strategy for treating various types of tumors. However, single-target PD-1/PD-L1 inhibitors frequently encounter primary resistance or secondary resistance, posing significant challenges to clinical treatment and creating an urgent need for novel therapeutic approaches. In this study, we designed and synthesized a dual PD-L1/JAK Inhibitor PJ27 for the first time, which showed significant and balanced inhibitory activities against PD-1/PD-L1 (IC50 = 414 nM) and JAK1 (IC50 = 786 nM). Besides, PJ27 exhibited remarkable in vitro immune activation effects. Furthermore, PJ27 potently and dose-dependently inhibited tumor growth in the LLC lung Cancer mouse model without obvious toxicity. Moreover, PJ27 enhanced the infiltration of CD3+ CD8+ and CD3+ CD4+ cells into the tumor microenvironment. Additionally, kinase spectrum analysis demonstrated that PJ27 possessed favorable selectivity towards JAK1. Collectively, PJ27 represented the first dual PD-L1/JAK Inhibitor deserving further research as a tumor immunotherapy agent.

Keywords

Dual inhibitor; JAK; PD-1/PD-L1; Tumor immunotherapy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-181663
    PD-1/PD-L1/JAK1 Inhibitor