Discovery of Pyrazole-Containing 4‑Arylindolines as Potent Small-Molecule Inhibitors of the Programmed Cell...

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 1, a potent immunomodulator previously reported by our group. Among these, compound J29 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, J29 effectively promoted T-cell proliferation and restored their ability to kill tumor cells. Moreover, J29 showed significantly improved metabolic stability in human liver microsomes (HLMs) compared with compound 1. These findings indicate that J29 represents a promising lead compound for the further development of small-molecule PD-1/PD-L1 interaction inhibitors.