2. Academic Validation
  3. Structure-Based Design of Dual-Acting Compounds Targeting Adenosine A2A Receptor and Histone Deacetylase as Novel Tumor Immunotherapeutic Agents

Structure-Based Design of Dual-Acting Compounds Targeting Adenosine A2A Receptor and Histone Deacetylase as Novel Tumor Immunotherapeutic Agents

  • J Med Chem. 2021 Nov 25;64(22):16573-16597. doi: 10.1021/acs.jmedchem.1c01155.
Wenzhong Yan 1,  Lijun Ling 2 3,  Yiran Wu 1,  Kexin Yang 2 3,  Ruiquan Liu 1,  Jinfeng Zhang 1 3,  Simeng Zhao 1,  Guisheng Zhong 1 3,  Suwen Zhao 1 3,  Hualiang Jiang 2 3 4,  Chengying Xie 4 5,  Jianjun Cheng 1
Affiliations

Affiliations

  • 1 iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • 2 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 4 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
PMID: 34783558 DOI: 10.1021/acs.jmedchem.1c01155
Abstract

Adenosine is an immunosuppressive factor in the tumor microenvironment mainly through activation of the A2A Adenosine Receptor (A2AR), which is a mechanism hijacked by tumors to escape immune surveillance. Small-molecule A2AR antagonists are being evaluated in clinical trials as immunotherapeutic agents, but their efficacy is limited as standalone therapies. To enhance the antitumor effects of A2AR antagonists, dual-acting compounds incorporating A2AR antagonism and histone deacetylase (HDAC) inhibitory actions were designed and synthesized, based on co-crystal structures of A2AR. Compound 24e (IHCH-3064) exhibited potent binding to A2AR (Ki = 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 A2AR and HDAC are potentially immunotherapeutic agents that are worth further exploring.

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