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的免疫激活。但是，肿瘤劫持了这种机制以避免免疫监测。该途径的关键酶，色氨酸2,3-二加氧酶（TDO）和吲哚胺2,3-二加氧酶（IDO）已建立了免疫检查点蛋白质。肿瘤增强其表达以阻断T细胞增殖并诱导T细胞死亡，从而避免免疫系统监测和肿瘤细胞迁移能力的增加。因此，抑制这些检查点通过基于小分子的疗法在癌细胞中的酶已成为潜在的免疫治疗性战略。从创新的方法开发的新代理商的迫切需求很高了解他们的基本化学和生物学，促进整体科学知识和最终帮助公众过着健康的生活。从一项联合基础科学研究中，我们确定了一个非 - 人类TDO中的催化l-色氨酸（L-TRP）结合位点，它比L-TRP的结合比较紧。催化血红素部位。新发现的L-TRP结合位点参与调节TDO活动和稳定性通过抑制泛素依赖性降解时，加载L-TRP时。这一发现激发了我们建议一个新发现的信号位点是用于药物开发的TDO脚跟的中心假设。该应用程序将满足识别蛋白质降解配体的关键需求，以探索其生物医学潜在的。为此，我们将以新颖的作用方式设计化合物，使信号稳定 TDO的位点或结合而不增强蛋白质稳定性。这些药物不会针对 TDO，但会破坏其降解信号。我们将评估有希望的化合物的影响在细胞模型中的人类TDO上，以验证创新方法和目标。最后，这项工作将开放设计针对免疫检查点蛋白质人类TDO的革命性新抑制剂的门。