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

文献类型：期刊论文

作者Liu, Chenglong2; Zhou, Feilong1; Yan, Ziqin1; Shen, Lian2; Zhang, Xichen1,3; He, Fenglian2; Wang, Heng2; Lu, Xiaojie1; Yu, Ker2; Zhao, Yujun1,3,4
刊名BRITISH JOURNAL OF PHARMACOLOGY
出版日期2021-05-04
页码20
ISSN号0007-1188
关键词immunotherapy PD-1/PD-L1 TGF-beta tumour immune microenvironment
DOI10.1111/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
源URL[http://119.78.100.183/handle/2S10ELR8/296609]  
专题新药研究国家重点实验室
通讯作者Zhao, Yujun; Zhu, Di
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Fudan Univ, Sch Pharm, Dept Pharmacol, 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.

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来源：上海药物研究所

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