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

doi:10.1021/acs.jmedchem.1c01155

	Structure-Based Design of Dual-Acting Compounds Targeting Adenosine A(2A) Receptor and Histone Deacetylase as Novel Tumor Immunotherapeutic Agents
	Yan, Wenzhong1 ; Ling, Lijun2,3 ; Wu, Yiran1 ; Yang, Kexin2,3 ; Liu, Ruiquan1 ; Zhang, Jinfeng1,3 ; Zhao, Simeng1 ; Zhong, Guisheng1,3 ; Zhao, Suwen1,3 ; Jiang, Hualiang2,3,4 ; Xie, Chengying 4,5; Cheng, Jianjun1
	2021-11-25
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
EISSN	1520-4804
卷号	64 期号:22
发表状态	已发表
DOI	10.1021/acs.jmedchem.1c01155
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.
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收录类别	SCI ; SCIE ; IC
语种	英语
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000754726000015
出版者	AMER CHEMICAL SOC
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/157678
专题	iHuman研究所_PI研究组_程建军组 iHuman研究所_公共科研平台_IT平台免疫化学研究所_特聘教授组_蒋华良组 iHuman研究所_PI研究组_赵素文组 iHuman研究所_PI研究组_钟桂生组生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Jiang, Hualiang; Xie, Chengying; Cheng, Jianjun
作者单位	1.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China 2.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
第一作者单位	iHuman研究所
通讯作者单位	免疫化学研究所; 生命科学与技术学院; iHuman研究所
第一作者的第一单位	iHuman研究所
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).
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).
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).