Design and development of HDAC11-specific chemical inhibitors for disease treatments

用于疾病治疗的 HDAC11 特异性化学抑制剂的设计和开发

基本信息

批准号：
10205726
负责人：
Hening Lin
金额：
$ 71.29万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10205726
关键词：
Acute Adverse effects Affect Autoimmune Diseases Biochemical Biological Biological Process CNS Demyelinating Autoimmune Diseases Cells Chemicals Chronic Chronic Progressive Multiple Sclerosis Clinical Clinical Trials Collaborations Data Deacetylase Deacetylation Development Disease Disease Management Enzyme Inhibitor Drugs Enzymes Experimental Autoimmune Encephalomyelitis Future Genetic Models Goals HDAC11 gene HDAC4 gene Health Healthcare Histone Deacetylase Immune Infiltration Interferon Type I Interferon-beta Interferons Knockout Mice Knowledge Laboratories Lysine Mediating Mission Modeling Multiple Sclerosis Mus Nerve Degeneration Pathogenesis Pathology Pharmaceutical Preparations Phase Physiological Proteomics Recombinant Interferon Relapsing-Remitting Multiple Sclerosis Reporting Research Research Support Role Severity of illness Side Signal Transduction Spinal Cord Symptoms Testing Therapeutic Time United States National Institutes of Health Universities Virus Diseases Washington Work acyl group alternative treatment base cell motility central nervous system demyelinating disorder design disability effective therapy fatty acylation improved in vivo inhibitor/antagonist insight mouse model multidisciplinary multiple sclerosis patient multiple sclerosis treatment nervous system disorder new therapeutic target novel prototype small molecule targeted treatment tool treatment strategy young adult

项目摘要

Project Summary This resubmission proposal aims to elucidate the role of a histone deacetylase, HDAC11, in diseases such as multiple sclerosis (MS), and to establish HDAC11 inhibition as a potentially effective new treatment strategy for diseases including MS. MS is a chronic, immune-mediated demyelinating disease of the central nervous system. Like many autoimmune disorders, it presently has no known cure, and current drugs available for managing this disease are only effective early on and are accompanied by many adverse effects. The disease mechanism of MS remains unclear, and no effective targeted therapy is available for chronic progressive MS. Our preliminary studies show that deletion of HDAC11 ameliorates clinical symptoms in a mouse model of MS. In parallel, we discovered a novel HDAC11 enzymatic activity that is >10,000-fold more efficient than its deacetylase activity. This novel activity allows us to begin to uncover physiologic substrates of HDAC11, which in turn will help to uncover the biological mechanisms of HDAC11’s actions. One of the goals of this research is to investigate how this newly discovered enzymatic activity underlies the immune-regulatory function of HDAC11 in MS. Knowledge gained from these studies will help to further understand the disease mechanism of MS and to develop better therapeutics. Because the discovery of a novel HDAC11 activity has enabled us to develop, for the first time, HDAC11-specific inhibitors, the chief objective is to further improve these inhibitors and test whether they can be used to treat diseases such as MS in our established mouse models. Our multidisciplinary team has expertise in all aspects needed to make this project successful. Overall, the proposed studies in this application will not only yield a better understanding of HDAC11’s function in health and diseases, but may also result in a first prototype targeted therapy for the treatment of chronic progressive MS, and possibly other diseases as well.

项目摘要该重新提出的建议旨在阐明组蛋白脱乙酰基酶HDAC11在此类疾病中的作用作为多发性硬化症（MS），并建立HDAC11作为潜在有效的新治疗策略用于包括MS在内的疾病。 MS是一种慢性免疫介导的中枢神经系统脱髓鞘疾病系统。像许多自身免疫性疾病一样，目前尚无已知治愈方法，目前可用于管理这种疾病仅在早期才有效，并且通过许多不利影响来完成。疾病 MS机制仍然不清楚，并且没有有效的靶向治疗可用于慢性进行性MS。我们的初步研究表明，HDAC11的缺失可以缓解MS小鼠模型中的临床症状。同时，我们发现了一种新型的HDAC11酶促活性，其效率比其效率高10,000倍脱乙酰基酶活性。这项新型活动使我们能够开始发现HDAC11的生理底物，反过来，将有助于发现HDAC11动作的生物学机制。这项研究的目标之一是为了研究这种新发现的酶活性是如何构成的 MS中的HDAC11。从这些研究中获得的知识将有助于进一步了解疾病机制 MS并开发更好的治疗剂。因为发现新颖的HDAC11活动使我们能够主要目标是首次发展HDAC11特异性抑制剂，是进一步改善这些抑制剂并测试它们是否可以用于治疗我们已建立的鼠标模型中的MS等疾病。我们的多学科团队在使该项目成功所需的各个方面都有专业知识。总体而言，本应用程序中的拟议研究不仅会更好地了解HDAC11在健康方面的功能和疾病，但也可能导致第一种原型治疗用于治疗慢性进行的治疗 MS，可能还有其他疾病。