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Structure-Based Design of Dual-Acting Compounds Targeting Adenosine A(2A) Receptor and Histone Deacetylase as Novel Tumor Immunotherapeutic Agents

文献类型：期刊论文

作者Yan, Wenzhong2; Ling, Lijun3,4; Wu, Yiran2; Yang, Kexin3,4; Liu, Ruiquan2; Zhang, Jinfeng2,4; Zhao, Simeng2; Zhong, Guisheng2,4; Zhao, Suwen2,4; Jiang, Hualiang1,3,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-11-25
卷号64期号:22页码:16573-16597
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c01155
通讯作者Jiang, Hualiang(hljiang@simm.ac.cn) ; Xie, Chengying(xiechengying818@simm.ac.cn) ; Cheng, Jianjun(chengjj@shanghaitech.edu.cn)
英文摘要Adenosine is an immunosuppressive factor in the tumor microenvironment mainly through activation of the A(2A) adenosine receptor (A(2A)R), which is a mechanism hijacked by tumors to escape immune surveillance. Small-molecule A(2A)R antagonists are being evaluated in clinical trials as immunotherapeutic agents, but their efficacy is limited as standalone therapies. To enhance the antitumor effects of A(2A)R antagonists, dual-acting compounds incorporating A(2A)R antagonism and histone deacetylase (HDAC) inhibitory actions were designed and synthesized, based on co-crystal structures of A(2A)R. Compound 24e (IHCH-3064) exhibited potent binding to A(2A)R (K-i = 2.2 nM) and selective inhibition of HDAC1 (IC50 = 80.2 nM), with good antiproliferative activity against tumor cell lines in vitro. Intraperitoneal administration of 24e (60 mg/kg, bid) inhibited mouse MC38 tumor growth with a tumor growth inhibition rate of 95.3%. These results showed that dual-acting compounds targeting A(2A)R and HDAC are potentially immunotherapeutic agents that are worth further exploring.
WOS关键词INHIBITOR ; HDAC ; LIGANDS ; GROWTH
资助项目Shanghai Municipal Government ; ShanghaiTech University
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000754726000015
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/300409]  
专题新药研究国家重点实验室
通讯作者Jiang, Hualiang; Xie, Chengying; Cheng, Jianjun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
2.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
3.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Yan, Wenzhong,Ling, Lijun,Wu, Yiran,et al. Structure-Based Design of Dual-Acting Compounds Targeting Adenosine A(2A) Receptor and Histone Deacetylase as Novel Tumor Immunotherapeutic Agents[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(22):16573-16597.
APA Yan, Wenzhong.,Ling, Lijun.,Wu, Yiran.,Yang, Kexin.,Liu, Ruiquan.,...&Cheng, Jianjun.(2021).Structure-Based Design of Dual-Acting Compounds Targeting Adenosine A(2A) Receptor and Histone Deacetylase as Novel Tumor Immunotherapeutic Agents.JOURNAL OF MEDICINAL CHEMISTRY,64(22),16573-16597.
MLA Yan, Wenzhong,et al."Structure-Based Design of Dual-Acting Compounds Targeting Adenosine A(2A) Receptor and Histone Deacetylase as Novel Tumor Immunotherapeutic Agents".JOURNAL OF MEDICINAL CHEMISTRY 64.22(2021):16573-16597.

入库方式： OAI收割

来源：上海药物研究所

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