靶向色氨酸-犬尿酸代谢中的关键双氧酶进行免疫调节和癌症化疗。
Targeting key dioxygenases in tryptophan-kynurenine metabolism for immunomodulation and cancer chemotherapy.
机构信息
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
出版信息
Drug Discov Today. 2015 May;20(5):609-17. doi: 10.1016/j.drudis.2014.11.007. Epub 2014 Dec 3.
Tryptophan to kynurenine metabolism is controlled by three distinct dioxygenase enzymes: tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1), and indoleamine 2,3-dioxygenase 2 (IDO2). Collectively, the activity of these enzymes contributes to tumour immune tolerance and immune dysregulation in a variety of disease pathologies, including cancer. Whereas IDO1 inhibitor drug design has been the focus of study for more than two decades (with novel compounds currently in Phase II clinical trials), only recently have the roles of TDO and IDO2 been elucidated in immunosuppression. Consequently, little comparative work on inhibitor cross-reactivity and selectivity has been performed. Here, we provide an overview of the current and future drug discovery landscape for targeting TDO, IDO1, and IDO2 (individually and collectively) for pharmacological intervention.
色氨酸到犬尿氨酸代谢受三种不同的加氧酶控制
色氨酸 2,3-加氧酶（TDO）、吲哚胺 2,3-加氧酶 1（IDO1）和吲哚胺 2,3-加氧酶 2（IDO2）。这些酶的活性共同导致肿瘤免疫耐受和多种疾病病理中的免疫失调，包括癌症。虽然 IDO1 抑制剂药物设计已经成为研究的焦点超过二十年（目前有新型化合物处于 II 期临床试验阶段），但 TDO 和 IDO2 在免疫抑制中的作用直到最近才被阐明。因此，对抑制剂交叉反应性和选择性的比较研究很少。在这里，我们提供了一个概述，介绍了针对 TDO、IDO1 和 IDO2（单独和联合）进行药理学干预的当前和未来的药物发现前景。
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