Discovery of Pyridinone Derivatives as Potent, Selective, and Orally Bioavailable Adenosine A2A Receptor Antagonists for Cancer Immunotherapy.
Discovery of Pyridinone Derivatives as Potent, Selective, and Orally Bioavailable Adenosine A2A Receptor Antagonists for Cancer Immunotherapy.
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DOI：
10.1021/acs.jmedchem.2c01860
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发表时间：
2023-03
影响因子：
7.3
通讯作者：
Chenyu Zhu;Shuyin Ze;Rong-Han Zhou;Xinyu Yang;Haojie Wang;Xiaolei Chai;Meimiao Fang;Mingyao Liu;Yonghui Wang;Weiqiang Lu;Qiong Xie
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作者：
Chenyu Zhu;Shuyin Ze;Rong-Han Zhou;Xinyu Yang;Haojie Wang;Xiaolei Chai;Meimiao Fang;Mingyao Liu;Yonghui Wang;Weiqiang Lu;Qiong Xie
最近的研究和临床证据有力地支持开发腺苷A2 A受体（A2 AR）拮抗剂作为癌症免疫治疗的新方法。通过筛选我们的内部化合物库，鉴定了具有弱A2 AR拮抗活性的吡啶酮命中化合物（1）。进一步的构效关系研究发现了一系列具有较强活性的吡啶酮衍生物。化合物38具有强效的A2 AR拮抗活性（IC 50 = 29.0 nM）、良好的小鼠肝微粒体代谢稳定性（t1/2 = 86.1 min）和出色的口服生物利用度（F = 86.1%）。值得注意的是，38通过下调免疫抑制分子（LAG-3和TIM-3）和上调效应分子（GZMB、IFNG和IL-2）有效地增强了体外T细胞的活化和杀伤能力。此外，38通过口服给药在MC 38肿瘤模型中表现出优异的体内抗肿瘤活性，肿瘤生长抑制（TGI）为56.0%，表明其作为癌症免疫治疗的新型A2 AR拮抗剂候选物的潜力。
Recent studies and clinical evidence have strongly supported the development of adenosine A2A receptor (A2AR) antagonists as novel approaches for cancer immunotherapy. By screening our in-house compound library, a pyridinone hit compound (1) with weak A2AR antagonistic activity was identified. Further structure-activity relationship studies revealed a series of pyridinone derivatives with strong potency. Compound 38 stood out with a potent A2AR antagonistic activity (IC50 = 29.0 nM), good mouse liver microsomal metabolic stability (t1/2 = 86.1 min), and excellent oral bioavailability (F = 86.1%). Of note, 38 effectively enhanced the activation and killing ability of T cells in vitro by down-regulation of immunosuppressive molecules (LAG-3 and TIM-3) and up-regulation of effector molecules (GZMB, IFNG, and IL-2). Moreover, 38 exhibited excellent in vivo antitumor activity with a tumor growth inhibition (TGI) of 56.0% in the MC38 tumor model via oral administration, demonstrating its potential as a novel A2AR antagonist candidate for cancer immunotherapy.