Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.

中文翻译：

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胶质母细胞瘤新型吲哚胺 2,3-双加氧酶 1 蛋白降解剂的鉴定和表征


吲哚胺 2,3-双加氧酶 1 (IDO1) 是一种有效的免疫抑制酶，可通过色氨酸代谢和非酶功能抑制抗肿瘤免疫反应。迄今为止，大多数 IDO1 靶向方法都集中于抑制色氨酸代谢。然而，此类药物未能改善癌症患者的总体生存率。在这里，我们开发并表征了可降解 IDO1 蛋白的蛋白水解靶向嵌合体 (PROTAC)。测试了 IDO1-PROTAC 对 IDO1 酶和非酶活性的影响。在筛选 IDO1-PROTAC 衍生物文库后，鉴定出一种化合物可以通过 cereblon 介导的蛋白酶体降解有效降解 IDO1 蛋白。 IDO1-PROTAC：(i) 在培养的人胶质母细胞瘤 (GBM) 细胞中抑制 IDO1 酶活性和 IDO1 介导的 NF-κB 磷酸化，(ii) 在体内降解颅内脑肿瘤内的 IDO1 蛋白，以及 (iii) 介导存活对患有明确脑肿瘤的小鼠有益。这项研究鉴定并鉴定了一种新的 IDO1 蛋白降解剂，该降解剂对胶质母细胞瘤患者具有治疗潜力。