Novel ubiquitin protease inhibitor for treating asthma

哮喘是影响全球3亿人的主要公共卫生问题。虽然没有治愈的方法， 症状可以用皮质类固醇和β-2激动剂来控制，这可能会产生有害的副作用。 对于类固醇抗药性和其他形式的哮喘，需要改进的靶向治疗。一种复杂的疾病， 哮喘导致慢性炎症、高反应性和呼吸道重塑，以及由以下因素驱动的免疫 Th2和TH17细胞参与了哮喘亚型的发病。这些免疫系统分泌的细胞因子 细胞作用于招募嗜酸性粒细胞和中性粒细胞，导致哮喘的病理；此外， Th2和Th17的反应最终导致炎症的进一步放大和升高。目标明确 抑制TH2和TH17分化和/或反应是这里治疗的一般方法 哮喘的潜在驱动因素。尤其是，泛素途径调节免疫反应，泛素- 基础药物在控制哮喘方面可能有用处。例如，E3连接酶瘙痒同时抑制TH2和 Nedd4家族相互作用蛋白1(Ndfip1)激活后Th17的分化和细胞因子的产生。 Progenra发现了小分子Ndfip1模拟物，它能够激活瘙痒，损害IL-4的产生 促进Treg而不是TH2细胞分化。最近，脱泛素酶USP4被证明是 稳定TH17特异性转录因子RORGammaT对TH17分化的关键作用及药理作用 抑制USP4可阻断TH17的分化。因此，可以通过以下方式选择性地靶向TH17和TH2的分化 调制USP4功能。因此，这里提出了发现和开发选择性小分子 USP4的抑制剂；这些有望限制TH17的分化，抑制炎症性哮喘 回应。此外，USP4抑制剂将与Progenra的小分子Ndfip1模拟物(Itch)结合使用 激活剂)选择性地损害TH17和TH2的分化。为了实现这一治疗目标，高吞吐量 将使用Progenra的筛选平台和220,000名成员进行USP4抑制剂的筛选 小分子文库。将对选定的HITS进行细胞概念验证分析，以评估其效果 相关体外模型对TH17分化和细胞因子产生的影响。在第二阶段，领导优化和 将对选定的抑制剂进行额外的临床前研究以确定它们调节USP4的能力 并能抑制相关小鼠模型的炎症反应。最终的商业目标是发展 可联合用于治疗(类固醇抗药性)哮喘的新型小分子药物。

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.