Cancer immunotherapy has achieved a leap from the laboratory to the clinic, especially for therapeutic applications based on programmed cell death-1 (PD-1) and its ligand (PD-L1) that target tumour immune escape and growth. At present, 13 PD-1/PD-L1 monoclonal antibodies (mAbs) have been approved as PD-1/PD-L1 inhibitors by the United States Food and Drug Administration (FDA). However, inherent limitations of mAbs, including poor bioavailability and immunogenicity, have led researchers to pursue alternatives and develop small-molecule inhibitors with low molecular weight. Biphenyl derivatives are small-molecule inhibitors of PD-1/PD-L1 with advantages of oral bioavailability, high tumour penetration and better pharmacokinetic properties. In this work, we review progress and structure-activity relationship analysis of biphenyl derivatives as PD-1/PD-L1 inhibitors. The conclusions could contribute to the design of PD-1/PD-L1 inhibitor candidates for cancer immunotherapy.

癌症免疫治疗实现了从实验室到临床的飞跃，特别是基于程序性细胞死亡1（PD-1）及其配体（PD-L1）针对肿瘤免疫逃逸和生长的治疗应用。目前，已有13种PD-1/PD-L1单克隆抗体（mAb）被美国食品药品监督管理局（FDA）批准为PD-1/PD-L1抑制剂。然而，单克隆抗体的固有局限性，包括较差的生物利用度和免疫原性，促使研究人员寻求替代品并开发低分子量的小分子抑制剂。联苯衍生物是PD-1/PD-L1的小分子抑制剂，具有口服生物利用度高、肿瘤穿透力强、药代动力学特性好的优点。在这项工作中，我们综述了联苯衍生物作为PD-1/PD-L1抑制剂的研究进展和构效关系分析。这些结论可能有助于设计用于癌症免疫治疗的 PD-1/PD-L1 候选抑制剂。