Discovery of a novel, potent and selective small-molecule inhibitor of PD-1/PD-L1 interaction with robust in vivo anti-tumour efficacy

doi:10.1111/bph.15457

	Discovery of a novel, potent and selective small-molecule inhibitor of PD-1/PD-L1 interaction with robust in vivo anti-tumour efficacy
	Liu, Chenglong 1; Zhou, Feilong 2; Yan, Ziqin 2; Shen, Lian 1; Zhang, Xichen 2,3; He, Fenglian 1; Wang, Heng 1; Lu, Xiaojie 2; Yu, Ker 1; Zhao, Yujun 2,3,4
刊名	BRITISH JOURNAL OF PHARMACOLOGY
	2021-05-04
页码	20
关键词	immunotherapy PD-1/PD-L1 TGF-beta tumour immune microenvironment
ISSN号	0007-1188
DOI	10.1111/bph.15457
通讯作者	Zhao, Yujun(yjzhao@simm.ac.cn) ; Zhu, Di(zhudi@fudan.edu.cn)
英文摘要	Background and purpose PD-1/PD-L1 antibodies have achieved great success in clinical treatment. However, monoclonal antibody drugs also have challenges, such as high manufacturing costs, poor diffusion, low oral bioavailability and limited penetration into tumour tissue. The development of small-molecule inhibitors of PD-1/PD-L1 interaction represents a promising perspective to overcome the above challenges in cancer immunotherapy. Experimental approach We explored structural activity relationships and used biochemical assays to generate a lead compound (ZE132). CD8+ T-cells killing assay and Ifng expression assay were used to verify the in vitro cellular activity of ZE132. Off-target study was performed to verify the selectivity. Syngeneic mouse models were used to verify the in vivo activity of ZE132 in tumour immune microenvironment (TIME). We also performed pharmacokinetics profiling in mice and The Cancer Genome Atlas database analysis. Key results ZE132 can effectively inhibit the PD-1/PD-L1 interactions in vitro, and it has a potent affinity to PD-L1. ZE132 shows robust anti-tumour effects in vivo, better than anti-PD-1 antibody. In the analysis of TIME, we found that ZE132 treatment promotes cytotoxic T-cell tumour infiltration and induces IL-2 expression. In addition, ZE132 elicits strong inhibitory effects on the mRNA expression of TGF-beta, which may serve as a potential biomarker to predict responsiveness to PD-1/PD-L1 immunotherapies. Conclusion and implications We identified a new lead compound ZE132 targeting PD-1/PD-L1 interactions, not only showing favourable drug-like properties in vitro and in vivo but also showing the advantage of overcoming the barrier of TIME compared to anti-PD-1 antibody.
资助项目	Science and Technology Commission of Shanghai Municipality[18431907100] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-005] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-004-010] ; Shanghai Science and Technology Commission[18JC1413800] ; Shanghai Science and Technology Commission[20430713600] ; Shanghai Science and Technology Commission[18ZR1403900] ; National Natural Science Foundation of China[81872724] ; National Natural Science Foundation of China[81872895] ; National Natural Science Foundation of China[82073682]
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY
WOS记录号	WOS:000646526600001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296609]
专题	中国科学院上海药物研究所
通讯作者	Zhao, Yujun; Zhu, Di
作者单位	1.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Sch Pharm, Beijing, Peoples R China 4.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou, Peoples R China 5.Fudan Univ, Key Lab Smart Drug Delivery, Shanghai, Peoples R China 6.Fudan Univ, Shanghai Engn Res Ctr Immune Therapy, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Liu, Chenglong,Zhou, Feilong,Yan, Ziqin,et al. Discovery of a novel, potent and selective small-molecule inhibitor of PD-1/PD-L1 interaction with robust in vivo anti-tumour efficacy[J]. BRITISH JOURNAL OF PHARMACOLOGY,2021:20.
APA	Liu, Chenglong.,Zhou, Feilong.,Yan, Ziqin.,Shen, Lian.,Zhang, Xichen.,...&Zhu, Di.(2021).Discovery of a novel, potent and selective small-molecule inhibitor of PD-1/PD-L1 interaction with robust in vivo anti-tumour efficacy.BRITISH JOURNAL OF PHARMACOLOGY,20.
MLA	Liu, Chenglong,et al."Discovery of a novel, potent and selective small-molecule inhibitor of PD-1/PD-L1 interaction with robust in vivo anti-tumour efficacy".BRITISH JOURNAL OF PHARMACOLOGY (2021):20.