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。虽然没有治愈方法， 可以用皮质类固醇和β2-激动剂来控制这些症状，这些激素和β2-激动剂可以产生有害的副作用。 对于激素抵抗型和其他形式的哮喘，需要改进的靶向治疗。一种复杂的疾病， 哮喘引起慢性炎症、高反应性和气道重塑， TH 2和TH 17细胞参与哮喘亚型的发病机制。这些免疫细胞分泌的细胞因子 细胞募集嗜酸性粒细胞和嗜中性粒细胞，导致哮喘的病理;此外， TH 2和TH 17反应最终导致炎症的进一步放大和升高。针对性 抑制TH 2和TH 17分化和/或应答是本文采用的治疗TH 2和TH 17的一般方法。 哮喘的潜在驱动因素。特别是，泛素途径调节免疫反应，泛素- 药物可能在控制哮喘方面具有效用。例如，E3连接酶Itch抑制TH 2和 通过Nedd 4家族相互作用蛋白1（Ndfip 1）激活后的TH 17分化和细胞因子产生。 Progenra已经鉴定出小分子Ndfip 1模拟物，其能够激活瘙痒，削弱IL-4的产生 并且促进Treg而不是TH 2细胞分化。最近，USP 4，一种去泛素化酶，已经被证明是 通过稳定TH 17特异性转录因子ROR γ T对TH 17分化至关重要， 抑制USP 4阻断了TH 17分化。因此，可以选择性地靶向TH 17和TH 2分化， 调节USP 4功能。因此，本文提出了发现和开发选择性小分子 USP 4的抑制剂;这些预期限制TH 17分化，抑制炎性哮喘 应答此外，USP 4抑制剂将与Progenra的小分子Ndfip 1模拟物（Itch 活化剂）以选择性地损害TH 17和TH 2分化。为了实现这一治疗目标， 将使用Progenra的筛选平台和220，000名成员进行USP 4抑制剂的筛选 小分子文库。将对选定的命中进行概念试验的细胞证明，以评价其效果 在相关体外模型中对TH 17分化和细胞因子产生的影响。在第二阶段，铅优化和 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USP 4的能力 在相关的小鼠模型中发挥作用并抑制炎症。最终的商业目标是发展 新的小分子药物，可用于联合治疗（类固醇耐药）哮喘。

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.