Discovery of a new inhibitor targeting PD-L1 for cancer immunotherapy

Fengling Wang, Wenling Ye, Shuang Wang, Yongxing He, Haiyang Zhong, Yuwei Wang, Yongchang Zhu, Jianting Han, Zhitong Bing, Shaoping Ji, Huanxiang Liu, Xiaojun Yao

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Blockade of the PD-1/PD-L1 immunologic checkpoint using monoclonal antibodies has provided breakthrough therapies against cancer in the recent years. Nevertheless, intrinsic disadvantages of therapeutic antibodies may limit their applications. Thus, blocking of the PD-1/PD-L1 interaction by small molecules may be a promising alternative for cancer immunotherapy. We used a docking-based virtual screening strategy to rapidly identify new small molecular inhibitors targeting PD-L1. We demonstrated that a small molecule compound (N-[2-(aminocarbonyl)phenyl][1,1′-biphenyl]-4-carboxamide [APBC]) could effectively interrupt the PD-1/PD-L1 interaction by directly binding to PD-L1, presenting the KD and IC50 values at low-micromolar level. Molecular docking study revealed that APBC may have function through a PD-L1 dimer-locking mechanism, occluding the PD-1 interaction surface of PD-L1. We further confirmed the ligand blocking activity and T cell-reinvigoration potency of APBC using cell-based assays. APBC could dose-dependently elevate cytokine secretions of the primary T-lymphocytes that are cocultured with cancer cells. Importantly, APBC displayed superior antitumor efficacy in hPD-L1 knock-in B16F10-bearing mouse model without the induction of observable liver toxicity. Analyses on the APBC-treated mice further revealed drastically elevated levels of infiltrating CD4+ and CD8+ T cells, and inflammatory cytokines production in tumor microenvironment. The APBC compound could serve as a privileged scaffold in the design of improved PD pathway modulators, thus providing us promising drug candidates for tumor immunotherapy.

Original languageEnglish
Pages (from-to)281-293
Number of pages13
Issue number3
Publication statusPublished - Mar 2021
Externally publishedYes


  • APBC
  • Cancer immunotherapy
  • Inhibitor
  • PD-1
  • PD-L1


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