Novel 4-Arylindolines Containing a Pyrido[3,2-]pyrimidine Moiety as the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction Inhibitors for Tumor Immunotherapy.

A series of pyrido[3,2-]pyrimidine-containing 4-arylindolines were identified as potent inhibitors of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by structural optimization of a 4-arylindoline precursor reported previously. Among them, compound was the most promising inhibitor, showing an IC value of 6.3 nM against the PD-1/PD-L1 interaction at the biochemical level. In T-cell tumor co-culture models, significantly promoted T-cell proliferation, activation, and infiltration into tumor spheres, demonstrating that it possessed excellent immunomodulatory activity. In addition, exhibited favorable in vivo antitumor activity in an LLC/PD-L1 tumor-bearing mouse model. Flow cytometry analysis verified that the in vivo antitumor efficacy of was dependent on the activation of the immune microenvironment. These findings suggest that can serve as a new starting point for the future development of small-molecule antitumor immunomodulators targeting the PD-1/PD-L1 axis.