Work

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

Year: 2025

Type: article

Abstract: 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 IC 50 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.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.5c00423