Targeting Tryptophan Dioxygenase Degradation for Suppression of Tumor Immune Evasion

摘要 色氨酸降解途径用于防止健康细胞中不受限制的免疫激活。 然而，肿瘤劫持了这种机制以逃避免疫监视。这一途径的关键酶， 色氨酸2，3-双加氧酶（TDO）和吲哚胺2，3-双加氧酶（IDO）是公认的免疫检查点 proteins.肿瘤增强其表达以阻断T细胞增殖并诱导T细胞死亡，从而避免T细胞死亡。 免疫系统监视和增加肿瘤细胞迁移能力。因此，抑制这些检查点 通过小分子疗法治疗癌细胞中的酶已经成为一种潜在的免疫疗法 战略迫切需要从创新方法中开发出具有坚实 了解其潜在的化学和生物学，以推进整体科学知识， 最终帮助公众健康长寿。从一项联合基础科学-临床研究中，我们发现了一种非- 人TDO中的催化L-色氨酸（L-Trp）结合位点，其与L-Trp的结合令人惊讶地比人TDO中的催化L-色氨酸（L-Trp）结合位点更紧密。 催化血红素位点新发现的L-Trp结合位点参与调节TDO活性和稳定性 通过抑制L-Trp负载时的泛素依赖性降解。这一发现启发我们提出 一个中心假设，即这个新发现的信号位点是药物开发TDO的阿喀琉斯之踵。 这一应用将填补关键需要，以确定蛋白质降解配体探索其生物医学 潜力为此，我们将设计一种新的作用模式的化合物， TDO位点或结合而不增强蛋白质稳定性。这些试剂将不靶向的催化活性， TDO，而是将破坏其劣化电阻信号。我们将评估有希望的化合物的效果 在细胞模型中对人类TDO进行研究，以验证创新方法和目标。最终，这部作品将开启 设计革命性的新抑制剂靶向免疫检查点蛋白人类TDO的大门。

ABSTRACT The tryptophan degradation pathway is used to prevent unrestrained immune activation in healthy cells. However, tumors hijack this mechanism to escape immune surveillance. The key enzymes of this pathway, tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), are established immune checkpoint proteins. Tumors enhance their expression to block T cell proliferation and induce T cell death, thereby avoiding immune system surveillance and increasing tumor cell migration capacity. Thus, inhibiting these checkpoint enzymes in cancer cells by small molecule-based therapies has emerged as a potential immunotherapeutic strategy. There is a critical need for new agents developed from an innovative approach with a solid understanding of their underlying chemistry and biology, to advance the overall scientific knowledge and to ultimately help the public live long healthy lives. From a joint basic science-clinical study we identified a non- catalytic L-tryptophan (L-Trp) binding site in human TDO, which binds L-Trp surprisingly much tighter than the catalytic heme site. The newly discovered L-Trp binding site is involved in regulating TDO activity and stability by suppressing ubiquitin-dependent degradation when loaded with L-Trp. This finding has inspired us to propose a central hypothesis that this newly discovered signaling site is an Achilles' heel of TDO for drug development. This application will fill the critical need to identify protein-degrading ligands for exploring their biomedical potential. Towards this end, we will design compounds with a novel mode of action that destabilize the signaling site of TDO or bind without enhancing the protein stability. These agents will not target the catalytic activity of TDO but instead will disrupt its degradation resistance signal. We will assess the effects of promising compounds on human TDO in cellular models to validate the innovative approach and target. In the end, this work will open the door for designing revolutionarily new inhibitors targeting the immune checkpoint protein human TDO.