{"_":"双重A/A腺苷受体拮抗剂及临床候选药物INCB106385的发现。","sub":["2A","2B"]}
{"_":"Discovery of Dual A/A Adenosine Receptor Antagonist and Clinical Candidate INCB106385.","sub":["2A","2B"]}
摘要(中文译文)
抑制免疫检查点通路使肿瘤细胞得以接管免疫调节功能，从而促进细胞生长和增殖。肿瘤微环境中腺苷生成增加，通过激活免疫细胞上的A腺苷受体而抑制免疫检查点控制。虽然最初为中枢神经系统适应症开发的A拮抗剂已进入肿瘤学领域，但其效力可能不足以在肿瘤微环境内局部高腺苷浓度下实现受体占据。在此，我们描述了INCB106385（）的发现，这是一种通过内部筛选工作鉴定出的强效双重A/A拮抗剂。该化合物对两种受体均具有高效力、良好的类药性质以及有限的中枢神经系统穿透性。在临床前研究中，它表现出稳健的跨物种药代动力学特征，并在多日CT26小鼠结肠癌模型中显示出显著疗效。这些发现支持INCB106385推进至用于癌症免疫治疗的1期临床试验（NCT04580485、NCT04989387）。
Abstract
Suppression of immune checkpoint pathways enables tumor cells to take over immunoregulatory functions, promoting cell growth and proliferation. Elevated adenosine production in the tumor microenvironment suppresses immune checkpoint control through activation of A adenosine receptors on immune cells. While A antagonists originally developed for CNS indications have entered oncology, their potency may be insufficient to challenge locally high adenosine concentrations within the tumor microenvironment for receptor occupancy. Here, we describe the discovery of INCB106385 (), a potent dual A/A antagonist identified from in-house screening efforts. Compound exhibits high potency at both receptors, favorable drug-like properties, and limited CNS penetration. In preclinical studies, it demonstrated robust pharmacokinetics across species and significant efficacy in a multiday CT26 mouse colon carcinoma model. These findings supported the advancement of INCB106385 into Phase 1 clinical trials (NCT04580485, NCT04989387) for cancer immunotherapy.
如何引用
AMA
Chao Qi, Matthew S McCammant, Yong Li, Wenyu Zhu, Zhiyong Yu, Peter Carlsen, et al. {"_":"Discovery of Dual A/A Adenosine Receptor Antagonist and Clinical Candidate INCB106385.","sub":["2A","2B"]}. Journal of medicinal chemistry. 2026; doi:10.1021/acs.jmedchem.6c00964.
APA
Chao Qi, Matthew S McCammant, Yong Li, Wenyu Zhu, Zhiyong Yu, Peter Carlsen, et al (2026). {"_":"Discovery of Dual A/A Adenosine Receptor Antagonist and Clinical Candidate INCB106385.","sub":["2A","2B"]}. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.6c00964
GB/T 7714
Chao Qi, Matthew S McCammant, Yong Li, Wenyu Zhu, Zhiyong Yu, Peter Carlsen, et al. {"_":"Discovery of Dual A/A Adenosine Receptor Antagonist and Clinical Candidate INCB106385.","sub":["2A","2B"]}[J]. Journal of medicinal chemistry, 2026 doi:10.1021/acs.jmedchem.6c00964.
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