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 (IC = 414 nM) and JAK1 (IC = 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.