Discovery of bromobenzyl phenyl ether derivative YPD-29B: a novel pre-clinical compound targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction.

Targeting the PD-1/PD-L1 immune checkpoint pathway with small molecules has exhibited great promise. Herein, to develop the inhibitors with good activity, pharmacokinetic properties and druggability, a novel series of halogens substituted derivatives at the 2-position of the biphenyl group were synthesized, screened, and their inhibitory activity against the PD-1/PD-L1 protein-protein interaction (PPI) was evaluated through a HTRF assay. Among them, YPD-29B exhibited potent activity with IC value of less than 1 pM. Furthermore, the PBMC-based PD-1/PD-L1 blockade bioassay revealed that YPD-29B could inhibit the PD-1/PD-L1 interaction and restore T-cell function with the concentration of 10 nM at the cellular level and with the IC value of 0.18 nM. However, the poor solubility of YPD-29B limited the evaluation of antitumor activity in vivo. Thus, the prodrug, sodium salt and hydrochloride of YPD-29B were designed and synthesized to conduct the animal experiments, revealing the obvious anti-melanoma activity of YPD-29B-Na with TGI of 64.11 % and weak toxicity on the blood index and the body weight compared with the positive control CTX. T lymphocyte infiltration markedly increased in tumors of the different treated groups, suggesting the activation of the immune system. Besides, molecular docking verified the rationality of the design. IMMH-010, as a prodrug of YPD-29B has been approved for clinical phase I by NMPA. We hope these above results could offer a novel perspective for the development of PD-1/PD-L1 small molecule inhibitors.