Design, synthesis, and structure-activity relationships of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as inhibitors of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint pathway

Small-molecule inhibitors of the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) immune checkpoint axis are emerging as a potential alternative therapeutic modality with distinct molecular characteristics as compared to the anti-PD-1 and anti-PD-L1 monoclonal antibodies. Herein, a series of 1,2,3,4-tetrahydroisoquinoline (THIQ)-3-carboxylic acid derivatives containing a 5-cyano-3-pyridinyl or 3-cyanophenyl appendage was designed by cyclizing the benzylamine to the ether linker of the (5-cyano-3-pyridinyl)methoxy moiety of our previously reported inhibitor LH1305. The new inhibitors were evaluated for inhibitory activity against the PD-1/PD-L1 protein-protein interaction (PPI) in a homogenous time-resolved fluorescence resonance energy transfer assay. Inhibitors with the 5-cyano-3-pyridinyl or 3-cyanophenyl appendages situated at the 1-position of the new THIQ scaffold (e.g., (1S,3S)-4e, LH1388, IC50 = 21.4 nM) demonstrated improved activity as compared to those with direct attachment to the nitrogen atom (e.g., (5)-1e, LH1352, IC50 = 329 nM). (1S,3S)-4e could serve as a promising lead compound for further optimization into potent inhibitors against the PD-1/PD-L1 PPI. [GRAPHICS] .