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Structure-Based Design of Dual-Acting Compounds Targeting Adenosine A2A Receptor and Histone Deacetylase as Novel Tumor Immunotherapeutic Agents
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-16 , 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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-16 , 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
Affiliation
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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.
中文翻译：
基于结构的靶向腺苷 A2A 受体和组蛋白脱乙酰酶的双效化合物作为新型肿瘤免疫治疗剂的设计
腺苷是肿瘤微环境中的一种免疫抑制因子，主要通过激活 A 2A腺苷受体 (A 2A R)，这是一种被肿瘤劫持以逃避免疫监视的机制。小分子 A 2A R 拮抗剂正在临床试验中作为免疫治疗剂进行评估，但其作为独立疗法的疗效有限。为了增强 A 2A R 拮抗剂的抗肿瘤作用，基于 A 2A R的共晶结构，设计并合成了具有 A 2A R 拮抗作用和组蛋白去乙酰化酶 (HDAC) 抑制作用的双效化合物。 化合物24e (IHCH-3064) ) 表现出与 A 2A的有效结合R ( K i = 2.2 nM) 和对 HDAC1 的选择性抑制 (IC 50 = 80.2 nM)，在体外对肿瘤细胞系具有良好的抗增殖活性。24e （60 mg/kg，bid）腹腔内给药抑制小鼠MC38肿瘤生长，肿瘤生长抑制率为95.3%。这些结果表明，靶向 A 2A R 和 HDAC 的双效化合物是潜在的免疫治疗药物，值得进一步探索。
更新日期：2021-11-25
中文翻译：
基于结构的靶向腺苷 A2A 受体和组蛋白脱乙酰酶的双效化合物作为新型肿瘤免疫治疗剂的设计
腺苷是肿瘤微环境中的一种免疫抑制因子，主要通过激活 A 2A腺苷受体 (A 2A R)，这是一种被肿瘤劫持以逃避免疫监视的机制。小分子 A 2A R 拮抗剂正在临床试验中作为免疫治疗剂进行评估，但其作为独立疗法的疗效有限。为了增强 A 2A R 拮抗剂的抗肿瘤作用，基于 A 2A R的共晶结构，设计并合成了具有 A 2A R 拮抗作用和组蛋白去乙酰化酶 (HDAC) 抑制作用的双效化合物。 化合物24e (IHCH-3064) ) 表现出与 A 2A的有效结合R ( K i = 2.2 nM) 和对 HDAC1 的选择性抑制 (IC 50 = 80.2 nM)，在体外对肿瘤细胞系具有良好的抗增殖活性。24e （60 mg/kg，bid）腹腔内给药抑制小鼠MC38肿瘤生长，肿瘤生长抑制率为95.3%。这些结果表明，靶向 A 2A R 和 HDAC 的双效化合物是潜在的免疫治疗药物，值得进一步探索。
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