Discovery of phenyl-linked symmetric small molecules as inhibitors of the programmed cell death-1/programmed cell death-ligand 1 interaction.

Programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) is one of the most promising targets in the field of immune checkpoint blockade therapy. Beginning with our exploration of linkers and structure-activity relationship research, we found that the aromatic ring could replace the linker and aryl group to maintain the satisfactory activity of classic triaryl scaffold inhibitor. Based on previous studies, we designed and synthesized a series of C 2 -symmetric phenyl-linked compounds, and further tail optimization afforded the inhibitors, which displayed promising inhibitory activity against the PD-1/PD-L1 interaction with IC 50 value at the single nanomolar range (C13–C15). Further cell-based PD-1/PD-L1 blockade bioassays indicated that these C 2 -symmetric molecules could significantly inhibit the PD-1/PD-L1 interaction at the cellular level and restore T cells' immune function at the safety concentrations. The discovery of these phenyl-linked symmetric small molecules showed the potential of simplified-linker and C 2 -symmetric strategy and provided a basis for developing symmetric small molecule inhibitors of PD-1/PD-L1 interaction. Moreover, C13 and C15 performed stable binding modes to PD-L1 dimeric after computational docking and dynamic simulation, which may serve as a good starting point for further development. [Display omitted] • A series of phenyl-linked symmetric compounds were synthesized and evaluated. • In cell-based PD-L1 blockade assay, C13–C15 showed promising RLU max and EC 50. • C13 and C15 significantly induced IFN-γ production at the safety concentrations. • Compound C13 and C15 performed stable binding mode to PD-L1 dimeric. [ABSTRACT FROM AUTHOR]