Discovery and Crystallography Study of Novel Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment

Current studies on PD-1/PD-L1 small-molecule inhibitors mainly focus on modifying the linker region between the biphenyl ring and amino acid side chains, or transforming the biphenyl ring into a benzodioxane structure. Herein, we designed and synthesized a series of compounds by introducing a tail at the terminal phenyl ring as small-molecule PD-1/PD-L1 inhibitors. Among them, compound <b>NPH16</b> exhibited the most potent PD-L1 inhibitory activity (IC₅₀ = 24.4 nM). The X-ray crystal structure further confirmed the high binding affinity of <b>NPH16</b> to PD-L1 dimer. In the HepG2/Jurkat T cell coculture model, <b>NPH16</b> promoted HepG2 cell apoptosis dose-dependently. In addition, <b>NPH16</b> showed excellent <i>in vivo</i> antitumor efficacy (TGI = 92.1%) in a Hepa1-6 mouse tumor model and increased CD8⁺ cells in tumor microenvironment. Importantly, <b>NPH16</b> possessed favorable pharmacokinetic properties with an oral bioavailability of 15.9%. Collectively, compound <b>NPH16</b> represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.