中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage

文献类型：期刊论文

作者Song, Zilan1,2,3,4; Liu, Bo2; Peng, Xia3; Gu, Wangting1; Sun, Yiming2; Xing, Li1; Xu, Yi5; Geng, Meiyu2,3,4; Ai, Jing2,4; Zhang, Ao1,2,3,4,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-11-25
卷号64期号:22页码:16687-16702
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c01422
通讯作者Ai, Jing(jai@simm.ac.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn)
英文摘要Blockade of immune checkpoint PD-1/PD-L1 has been a promising anticancer strategy; however, clinically available PD-1/PD-L1 small-molecule inhibitors are lacking. In view of the high potency of compound 2 (BMS-1002), structural fine tuning of the methoxy linkage together with diverse modification in the solvent interaction region was conducted. A series of novel derivatives featuring a difluoromethyleneoxy linkage were designed. Compound 43 was identified as the most promising PD-1/PD-L1 inhibitor with an IC50 value of 10.2 nM in the HTRF assay. This compound is capable of promoting CD8(+) T cell activation through inhibiting PD-1/PD-L1 cellular signaling. Moreover, in the Hepa1-6 syngeneic mouse model, administration of compound 43 at 1 mg/kg dosage promoted CD8(+) T cell activation and delayed the tumor growth with good tolerance. Notably, the tumor in one mouse of the compound 43-treated group was completely regressed. These results indicate that compound 43 is a promising candidate worthy of further investigation.
WOS关键词SMALL-MOLECULE INHIBITORS ; DERIVATIVES ; DISCOVERY
资助项目National Natural Science Foundation of China[81773565] ; National Natural Science Foundation of China[82173653] ; Natural Science Foundation of China for Innovation Research Group[81821005] ; Shanghai Jiao Tong University[AF1700037] ; Shanghai Jiao Tong University[WF220217002] ; Shanghai Jiao Tong University[WF540162618] ; Shanghai Jiao Tong University[WH101117001]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000754726000022
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/300448]  
专题新药研究国家重点实验室
通讯作者Ai, Jing; Zhang, Ao
作者单位1.Shanghai Jiao Tong Univ, Pharm X Ctr, Sch Pharm, Shanghai 200240, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Shanghai Pinghe Sch, Shanghai 201206, Peoples R China
6.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Song, Zilan,Liu, Bo,Peng, Xia,et al. Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(22):16687-16702.
APA Song, Zilan.,Liu, Bo.,Peng, Xia.,Gu, Wangting.,Sun, Yiming.,...&Zhang, Ao.(2021).Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage.JOURNAL OF MEDICINAL CHEMISTRY,64(22),16687-16702.
MLA Song, Zilan,et al."Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage".JOURNAL OF MEDICINAL CHEMISTRY 64.22(2021):16687-16702.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。