Discovery of a new inhibitor targeting PD-L1 for cancer immunotherapy
| Autor: | Xiao-Jun Yao, Wang Fengling, Shaoping Ji, Yuwei Wang, Huanxiang Liu, Shuang Wang, Han Jianting, Yong-Xing He, Haiyang Zhong, Zhitong Bing, Wenling Ye, Yongchang Zhu |
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| Rok vydání: | 2020 |
| Předmět: |
CD4-Positive T-Lymphocytes
Models Molecular Cancer Research medicine.medical_treatment Melanoma Experimental APBC Cancer immunotherapy APBC N-[2-(aminocarbonyl)phenyl][1 1′-biphenyl]-4-carboxamide GPT glutamic pyruvic transaminase B7-H1 Antigen Mice Antineoplastic Agents Immunological Drug Discovery PD-1 Immune Checkpoint Inhibitors biology Chemistry lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Small molecule Gene Expression Regulation Neoplastic Immunotherapy IHC immunohistochemistry Protein Binding PD-L1 FACS fluorescence activated cell sorter Original article Inhibitor medicine.drug_class DEGs differentially expressed genes SP standard extra precision BMS Bristol-Myers Squibb SPR surface plasmon resonance Monoclonal antibody GOT glutamic oxaloacetic transaminase lcsh:RC254-282 Structure-Activity Relationship Cell Line Tumor medicine Animals Humans HTRF homogenous time-resolved fluorescence ALB albumin Tumor microenvironment ALP alkaline phosphatase Xenograft Model Antitumor Assays Disease Models Animal RNA-seq RNA-sequencing mAbs monoclonal antibody Docking (molecular) TILs tumor infiltrating lymphocytes Cancer cell biology.protein Cancer research |
| Zdroj: | Neoplasia (New York, N.Y.) Neoplasia: An International Journal for Oncology Research, Vol 23, Iss 3, Pp 281-293 (2021) |
| ISSN: | 1476-5586 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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