基于结构的双重作用化合物设计，靶向腺苷 A 受体和组蛋白去乙酰化酶作为新型肿瘤免疫治疗药物。

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

机构信息

iHuman Institute, ShanghaiTech University, Shanghai 201210, China.

Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.

出版信息

J Med Chem. 2021 Nov 25;64(22):16573-16597. doi: 10.1021/acs.jmedchem.1c01155. Epub 2021 Nov 16.

DOI:10.1021/acs.jmedchem.1c01155

PMID:34783558

Abstract

Adenosine is an immunosuppressive factor in the tumor microenvironment mainly through activation of the A adenosine receptor (AR), which is a mechanism hijacked by tumors to escape immune surveillance. Small-molecule AR antagonists are being evaluated in clinical trials as immunotherapeutic agents, but their efficacy is limited as standalone therapies. To enhance the antitumor effects of AR antagonists, dual-acting compounds incorporating AR antagonism and histone deacetylase (HDAC) inhibitory actions were designed and synthesized, based on co-crystal structures of AR. Compound (IHCH-3064) exhibited potent binding to AR ( = 2.2 nM) and selective inhibition of HDAC1 (IC = 80.2 nM), with good antiproliferative activity against tumor cell lines in vitro. Intraperitoneal administration of (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 AR and HDAC are potentially immunotherapeutic agents that are worth further exploring.

摘要

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 腺苷受体 (AR) 起作用，而 AR 是肿瘤逃避免疫监视的一种机制。小分子 AR 拮抗剂作为免疫治疗药物正在临床试验中进行评估，但作为单一疗法，其疗效有限。为了增强 AR 拮抗剂的抗肿瘤作用，基于 AR 共晶结构，设计并合成了同时具有 AR 拮抗作用和组蛋白去乙酰化酶 (HDAC) 抑制作用的双重作用化合物。化合物 (IHCH-3064) 对 AR 具有很强的结合能力 ( = 2.2 nM)，对 HDAC1 具有选择性抑制作用 (IC = 80.2 nM)，对体外肿瘤细胞系具有良好的增殖活性。腹腔内给予 (60 mg/kg，bid) 可抑制小鼠 MC38 肿瘤生长，肿瘤生长抑制率为 95.3%。这些结果表明，针对 AR 和 HDAC 的双重作用化合物是有潜力的免疫治疗药物，值得进一步探索。