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

doi:10.1016/j.neo.2021.01.001

	Discovery of a new inhibitor targeting PD-L1 for cancer immunotherapy
	Wang, Fengling 2,3,4; Ye, Wenling 4; Wang, Shuang 2,3; He, Yongxing 5; Zhong, Haiyang 2,3; Wang, Yuwei 6; Zhu, Yongchang 2,3; Han, Jianting 2,3; Bing, Zhitong 7; Ji, Shaoping 4
刊名	NEOPLASIA
	2021-03-01
卷号	23 期号:3 页码:281-293
关键词	PD-1 PD-L1 Inhibitor APBC Cancer immunotherapy
ISSN号	1476-5586
DOI	10.1016/j.neo.2021.01.001
通讯作者	Liu, Huanxiang(hxliu@lzu.edu.cn) ; Yao, Xiaojun(xjyao@lzu.edu.cn)
英文摘要	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 K-D 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.
资助项目	National Natural Science Foundation of China[21775060] ; Shaanxi University of Chinese Medicine[2020XG01]
WOS研究方向	Oncology
语种	英语
出版者	ELSEVIER SCIENCE INC
WOS记录号	WOS:000623868500001
资助机构	National Natural Science Foundation of China ; Shaanxi University of Chinese Medicine
内容类型	期刊论文
源URL	[http://119.78.100.186/handle/113462/137763]
专题	中国科学院近代物理研究所
通讯作者	Liu, Huanxiang; Yao, Xiaojun
作者单位	1.Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macao, Peoples R China 2.Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou, Peoples R China 3.Lanzhou Univ, Dept Chem, Lanzhou, Peoples R China 4.Henan Univ, Sch Basic Med Sci, Inst Biomed Informat, Joint Natl Lab Antibody Drug Engn,Cell Signal Tra, Kaifeng, Peoples R China 5.Lanzhou Univ, Sch Life Sci, Key Lab Cell Act & Stress Adaptat, Minist Educ, Lanzhou, Peoples R China 6.Shaanxi Univ Chinese Med, Coll Pharm, Xianyang, Peoples R China 7.Chinese Acad Sci, Inst Modern Phys, Lanzhou, Peoples R China 8.Lanzhou Univ, Sch Pharm, Lanzhou, Peoples R China
推荐引用方式 GB/T 7714	Wang, Fengling,Ye, Wenling,Wang, Shuang,et al. Discovery of a new inhibitor targeting PD-L1 for cancer immunotherapy[J]. NEOPLASIA,2021,23(3):281-293.
APA	Wang, Fengling.,Ye, Wenling.,Wang, Shuang.,He, Yongxing.,Zhong, Haiyang.,...&Yao, Xiaojun.(2021).Discovery of a new inhibitor targeting PD-L1 for cancer immunotherapy.NEOPLASIA,23(3),281-293.
MLA	Wang, Fengling,et al."Discovery of a new inhibitor targeting PD-L1 for cancer immunotherapy".NEOPLASIA 23.3(2021):281-293.