Targeting Tryptophan Dioxygenase Degradation for Suppression of Tumor Immune Evasion

靶向色氨酸双加氧酶降解抑制肿瘤免疫逃避

基本信息

批准号：
10557210
负责人：
Ryan A Altman
金额：
$ 16.96万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557210
关键词：
Active Learning Active Sites Affinity Amino Acids Basic Science Binding Binding Sites Biochemical Biological Assay Biology Cell Death Cell model Cell physiology Cells Chemistry Clinical Research Clinical Trials Degradation Pathway Dioxygenases Docking Drug Industry Enzyme-Linked Immunosorbent Assay Enzymes FDA approved Future Gallbladder Carcinoma Head and Neck Squamous Cell Carcinoma Heme Human Immune Immune Targeting Immune checkpoint inhibitor Immune system Immunologic Surveillance Immunomodulators Immunotherapeutic agent In Vitro Institution Invaded Isoenzymes Joints Knowledge Lead Ligands Machine Learning Malignant Neoplasms Measures Mesothelioma Metabolic Multiple Myeloma New Agents Non-Small-Cell Lung Carcinoma Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pilot Projects Proliferating Prosthesis Proteins Resistance Series Signal Transduction Site Small Cell Carcinoma Solid Structure T-Cell Proliferation T-Lymphocyte Therapeutic Tissues Tryptophan Tryptophan 2,3 Dioxygenase Tryptophanase Tumor Cell Line Tumor Cell Migration Tumor Escape Tumor Immunity Tumor Suppression Ubiquitin Ubiquitination Work adaptive immune response analog bladder Carcinoma cancer therapy checkpoint inhibition design drug development enzyme pathway immune activation immune checkpoint indoleamine inhibitor innovation leukemia meter migration neoplastic cell novel preclinical trial prevent protein degradation response sarcoma scaffold small molecule therapeutic development tool tumor virtual

项目摘要

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.

抽象的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，肿瘤会劫持这种机制来逃避免疫监视。该途径的关键酶，色氨酸2,3-双加氧酶(TDO)和吲哚胺2,3-双加氧酶(IDO)，是建立的免疫检查点蛋白质。肿瘤增强其表达以阻止 T 细胞增殖并诱导 T 细胞死亡，从而避免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基于小分子的疗法来抑制癌细胞中的酶已成为一种潜在的免疫治疗方法战略。迫切需要通过创新方法开发具有坚实基础的新药物了解其基础化学和生物学，以提高整体科学知识并最终帮助公众健康长寿。从一项基础科学与临床联合研究中，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 的结合比催化血红素位点。新发现的L-Trp结合位点参与调节TDO活性和稳定性当加载 L-Trp 时，通过抑制泛素依赖性降解。这一发现启发我们提出一个中心假设是，这个新发现的信号位点是药物开发中 TDO 的致命弱点。该应用将满足识别蛋白质降解配体以探索其生物医学的关键需求潜在的。为此，我们将设计具有新颖作用模式的化合物，以破坏信号传导的稳定性 TDO 位点或结合而不增强蛋白质稳定性。这些试剂不会针对催化活性 TDO反而会扰乱其抗退化信号。我们将评估有前景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，这部作品将开启为设计针对免疫检查点蛋白人 TDO 的革命性新型抑制剂打开了大门。