Asthma is a major public health problem affecting 300 million people worldwide. While no cure is available, symptoms can be managed with corticosteroids and ?2-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.
Asthma is a complex disease, driven by T cells of the immune system that activate inflammatory cytokine secretion, causing asthma symptoms. Progenra has discovered small molecule ubiquitin pathway modulators that can reduce cytokine production by interfering with the T cells. A second ubiquitin pathway enzyme, USP4, has been found to activate T-cell dependent cytokine production. In this project, inhibitors of USP4 will be developed to use alone or in combination with the original T cell modulators to eradicate the symptoms of asthma produced by inflammatory cytokines; the combination treatment is expected to be very powerful.
