Discovery and Crystallography Study of Novel Biphenyl Ether and Oxadiazole Thioether (Non-Arylmethylamine)-Based Small-Molecule PD-1/PD-L1 Inhibitors as Immunotherapeutic Agents

Abstract

Current small-molecule PD-1/PD-L1 inhibitors are mainly based on the arylmethylamine/biphenyl core scaffold. Herein, we designed for the first time a series of non-arylmethylamine analogues (oxadiazole thioether derivatives) as small-molecule PD-1/PD-L1 inhibitors. Among them, compound <b>LP23</b> exhibited the most potent PD-L1 inhibitory activity with an IC₅₀ of 16.7 nM, 3.2-fold better than the lead <b>BMS-202</b> (IC₅₀ = 53.6 nM). The X-ray crystal structure of <b>LP23</b> in complex with PD-L1 was solved at a resolution of 2.6 Å, which further confirmed the high binding affinity of <b>LP23</b> to PD-L1. In the HepG2/Jurkat T cell co-culture model, <b>LP23</b> effectively promoted HepG2 cell death by restoring the immune function of T cells. In addition, <b>LP23</b> showed excellent <i>in vivo</i> antitumor efficacy (TGI = 88.6% at 30 mg/kg) and benign toxicity profiles in a B16-F10 tumor model by modulating PD-L1. In summary, <b>LP23</b> represents the first non-arylmethylamine-based small-molecule PD-1/PD-L1 inhibitor worthy of further investigation.