Novel ubiquitin protease inhibitor for treating asthma

用于治疗哮喘的新型泛素蛋白酶抑制剂

• 批准号: 9200067
• 负责人: Kumar Suresh
• 金额: $ 20.59万
• 依托单位: PROGENRA, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-06 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9200067
• 关键词: Adrenal Cortex Hormones; Adverse effects; Affect; Agonist; American; Animal Model; Asthma; Biological Assay; Cell Differentiation process; Cells; Chronic; Complex; Development; Digit structure; Disease; Disease model; Down-Regulation; Drug Design; Economic Burden; Enzymes; Family; Goals; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Impairment; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Interleukin-4; Interleukin-5; Irrigation; Lead; Liquid substance; Lung; Lung Inflammation; Messenger RNA; Mus; Mutation; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Play; Production; Protease Inhibitor; Proteins; Public Health; Quality of life; Recruitment Activity; Regulatory T-Lymphocyte; Research Personnel; Rheumatic Heart Disease; Role; Serum; Societies; Sputum; Steroid Resistance; Steroid-resistant asthma; Symptoms; System; T-Lymphocyte; Testing; Therapeutic; Ubiquitin; airway hyperresponsiveness; airway remodeling; asthmatic; asthmatic patient; base; cell type; counterscreen; cytokine; enzyme pathway; eosinophil; high throughput screening; improved; in vitro Model; inhibitor/antagonist; innovation; loss of function; member; mimetics; mouse model; multicatalytic endopeptidase complex; neurotensin mimic 1; neutrophil; novel; peripheral blood; preclinical evaluation; preclinical study; response; screening; small molecule; small molecule inhibitor; small molecule libraries; targeted treatment; transcription factor; ubiquitin-protein ligase

Asthma is a major public health problem affecting 300 million people worldwide. While no cure is available, symptoms can be managed with corticosteroids and β2-agonists, which can exert deleterious side effects. Improved, targeted therapies are needed for steroid-resistant and other forms of asthma. A complex disease, asthma entails chronic inflammation, hyper-reactivity, and remodeling of the airways, and immunity driven by TH2 and TH17 cells contributes to the pathogenesis of asthma subtypes. Cytokines secreted by these immune cells act to recruit eosinophils and neutrophils, leading to the pathology of asthma; further, crosstalk between TH2 and TH17 responses ultimately leads to further amplification and elevation of inflammation. Targeted suppression of TH2 and TH17 differentiation and/or responses is the general approach taken here for treating the underlying drivers of asthma. In particular, the ubiquitin pathway regulates immune responses, and ubiquitin- based drugs may have utility in controlling asthma. For example, the E3 ligase Itch suppresses both TH2 and TH17 differentiation and cytokine production upon activation by Nedd4-family interacting protein 1 (Ndfip1). Progenra has identified small molecule Ndfip1 mimetics which are able to activate Itch, impairing IL-4 production and promoting Treg rather than TH2 cell differentiation. Recently, USP4, a deubiquitylase, has been shown to be critical for TH17 differentiation by stabilizing TH17 specific transcription factor RORgammaT, and pharmacological inhibition of USP4 blocks TH17 differentiation. Thus, one can selectively target TH17 and TH2 differentiation by modulating USP4 function. It is therefore proposed here to discover and develop selective small molecule inhibitors of USP4; these are expected to limit TH17 differentiation, dampening inflammatory asthmatic responses. In addition, USP4 inhibitors will be combined with Progenra's small molecule Ndfip1 mimetics (Itch activators) to selectively impair TH17 and TH2 differentiation. To accomplish this therapeutic goal, high throughput screening for USP4 inhibitors will be conducted employing Progenra's screening platform and 220,000 member small molecule library. Cellular proof of concept assays will be conducted on selected hits to evaluate their effect on TH17 differentiation and cytokine production in relevant in vitro models. In Phase II, lead optimization and additional preclinical studies will be performed with selected inhibitors to ascertain their ability to modulate USP4 functions and to dampen inflammation in relevant mouse models. The ultimate commercial goal is the development of novel small molecule agents that can be used in combination to treat (steroid resistant) asthma.

哮喘是影响全球3亿人的主要公共卫生问题。虽然无法治愈，但 可以用皮质类固醇和β2激动剂来治疗症状，这些症状可以执行有害的副作用。 需要改善类固醇和其他形式的哮喘的靶向疗法。一种复杂的疾病， 哮喘需要慢性感染，过度反应性和气道重塑，并进行免疫驱动 Th2和Th17细胞有助于哮喘亚型的发病机理。这些免疫分泌的细胞因子 细胞起作用嗜酸性粒细胞和中性粒细胞，导致哮喘的病理。此外，跨越之间的串扰 TH2和TH17的反应最终导致炎症的进一步扩增和升高。目标 抑制Th2和Th17分化和/或反应是这里采用的一般方法 哮喘的基础驱动因素。特别是，泛素途径调节免疫反应和泛素 - 基于的药物可能具有控制哮喘的效用。例如，E3连接酶瘙痒均可抑制TH2和 NEDD4-家庭相互作用蛋白1（NDFIP1）激活后Th17分化和细胞因子产生。 后代已经确定了能够激活瘙痒的小分子NDFIP1模拟物，损害了IL-4的产生 并促进Treg而不是Th2细胞分化。最近，usp4是一种去泛素层，已被证明是 通过稳定Th17特异性转录因子rorgammat和药品，对Th17分化至关重要 抑制USP4阻止Th17分化。那可以通过 调节USP4功能。因此，这里建议发现和发展选择性的小分子 USP4的抑制剂；这些预计将限制Th17的分化，使炎症性哮喘发作 回答。此外，USP4抑制剂将与后代的小分子NDFIP1 Mimetics合并（瘙痒 激活剂）选择性损害Th17和Th2分化。为了实现这一治疗目标，高吞吐量 将对使用Gepenra的筛选平台和220,000名成员进行USP4抑制剂的筛查 小分子库。蜂窝概念评估将对选定的命中进行评估以评估其效果 关于相关体外模型中的Th17分化和细胞因子产生。在第二阶段，铅优化和 将使用选定的抑制剂进行其他临床前研究，以确定其调节USP4的能力 相关小鼠模型中的功能和湿注射。最终的商业目标是发展 可用于治疗（类固醇）哮喘的新型小分子剂的新型小分子剂。