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

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.