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

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 LP23 exhibited the most potent PD-L1 inhibitory
activity with an IC50 of 16.7 nM, 3.2-fold better than
the lead BMS-202 (IC50 = 53.6 nM). The X-ray
crystal structure of LP23 in complex with PD-L1 was solved
at a resolution of 2.6 Å, which further confirmed the high binding
affinity of LP23 to PD-L1. In the HepG2/Jurkat T cell
co-culture model, LP23 effectively promoted HepG2 cell
death by restoring the immune function of T cells. In addition, LP23 showed excellent in vivo 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, LP23 represents
the first non-arylmethylamine-based small-molecule PD-1/PD-L1 inhibitor
worthy of further investigation.