Discovery of Pyrazole-Containing 4-Arylindolines as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

The development of small-molecule inhibitors targeting the programmed cell death-1-(PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a promising strategy in tumor immunotherapy. In this study, a series of 4-arylindoline derivatives containing a pyrazole moiety were designed and synthesized through a medicinal chemistry campaign based on compound <b>1</b>, a potent immunomodulator previously reported by our group. Among these, compound <b>J29</b> was identified as the most promising inhibitor, exhibiting an IC₅₀ value of 5.5 nM against the PD-1/PD-L1 interaction in a biochemical assay. In coculture models of tumor cells and T cells, <b>J29</b> effectively promoted T-cell proliferation and restored their ability to kill tumor cells. Moreover, <b>J29</b> showed significantly improved metabolic stability in human liver microsomes (HLMs) compared with compound <b>1</b>. These findings indicate that <b>J29</b> represents a promising lead compound for the further development of small-molecule PD-1/PD-L1 interaction inhibitors.