2. Academic Validation
  3. Discovery of a new inhibitor targeting PD-L1 for cancer immunotherapy

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

  • Neoplasia. 2021 Mar;23(3):281-293. doi: 10.1016/j.neo.2021.01.001.
Fengling Wang 1,  Wenling Ye 2,  Shuang Wang 3,  Yongxing He 4,  Haiyang Zhong 3,  Yuwei Wang 5,  Yongchang Zhu 3,  Jianting Han 3,  Zhitong Bing 6,  Shaoping Ji 2,  Huanxiang Liu 7,  Xiaojun Yao 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China; Institute of Biomedical Informatics, Joint National Laboratory for Antibody Drug Engineering, Cell Signal Transduction Laboratory, School of Basic Medical Sciences, Henan University, Kaifeng, China.
  • 2 Institute of Biomedical Informatics, Joint National Laboratory for Antibody Drug Engineering, Cell Signal Transduction Laboratory, School of Basic Medical Sciences, Henan University, Kaifeng, China.
  • 3 State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China.
  • 4 Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China.
  • 5 College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China.
  • 6 Institute of Modern Physics of Chinese Academy of Sciences, Lanzhou, China.
  • 7 School of Pharmacy, Lanzhou University, Lanzhou, China. Electronic address: [email protected].
  • 8 State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China. Electronic address: [email protected].
PMID: 33529880 DOI: 10.1016/j.neo.2021.01.001
Abstract

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.

Keywords

APBC; Cancer immunotherapy; Inhibitor; PD-1; PD-L1.

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