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：
10360661
负责人：
Hening Lin
金额：
$ 69.75万
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/10360661
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 Persons 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 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.

项目概要该重新提交提案旨在阐明组蛋白脱乙酰酶 HDAC11 在疾病中的作用，例如治疗多发性硬化症 (MS)，并将 HDAC11 抑制确立为潜在有效的新治疗策略多发性硬化症（MS）是一种慢性、免疫介导的中枢神经系统脱髓鞘疾病。与许多自身免疫性疾病一样，目前尚无已知的治疗方法，目前也没有可用的药物。控制这种疾病仅在早期有效，并且伴随着许多不良反应。 MS的发病机制尚不清楚，慢性进展型MS尚无有效的靶向治疗方法。我们的初步研究表明，HDAC11 的缺失可改善 MS 小鼠模型的临床症状。与此同时，我们发现了一种新型 HDAC11 酶活性，其效率比其高 10,000 倍以上。这种新颖的活性使我们能够开始揭示 HDAC11 的生理底物，反过来将有助于揭示 HDAC11 作用的生物学机制是这项研究的目标之一。研究这种新发现的酶活性如何成为免疫调节功能的基础 HDAC11 在 MS 中的作用从这些研究中获得的知识将有助于进一步了解疾病机制。因为新的 HDAC11 活性的发现使我们能够首次开发HDAC11特异性抑制剂，主要目标是进一步改进这些抑制剂并在我们建立的小鼠模型中测试它们是否可以用于治疗多发性硬化症等疾病。多学科团队拥有使该项目成功所需的各个方面的专业知识。本申请中提出的研究不仅可以更好地了解 HDAC11 在健康方面的功能和疾病，但也可能导致第一个原型靶向治疗用于治疗慢性进行性多发性硬化症，可能还有其他疾病。