Novel ubiquitin protease inhibitor for treating asthma

Period of Performance: 07/06/2016 - 06/30/2017

$206K

Phase 1 SBIR

Recipient Firm

Progenra, Inc.
MALVERN, PA 19355
Principal Investigator

Abstract

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 byTH2 and TH17 cells contributes to the pathogenesis of asthma subtypes. Cytokines secreted by these immunecells act to recruit eosinophils and neutrophils, leading to the pathology of asthma; further, crosstalk betweenTH2 and TH17 responses ultimately leads to further amplification and elevation of inflammation. Targetedsuppression of TH2 and TH17 differentiation and/or responses is the general approach taken here for treatingthe 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 andTH17 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 productionand promoting Treg rather than TH2 cell differentiation. Recently, USP4, a deubiquitylase, has been shown to becritical for TH17 differentiation by stabilizing TH17 specific transcription factor RORgammaT, and pharmacologicalinhibition of USP4 blocks TH17 differentiation. Thus, one can selectively target TH17 and TH2 differentiation bymodulating USP4 function. It is therefore proposed here to discover and develop selective small moleculeinhibitors of USP4; these are expected to limit TH17 differentiation, dampening inflammatory asthmaticresponses. In addition, USP4 inhibitors will be combined with Progenra's small molecule Ndfip1 mimetics (Itchactivators) to selectively impair TH17 and TH2 differentiation. To accomplish this therapeutic goal, high throughputscreening for USP4 inhibitors will be conducted employing Progenra's screening platform and 220,000 membersmall molecule library. Cellular proof of concept assays will be conducted on selected hits to evaluate their effecton TH17 differentiation and cytokine production in relevant in vitro models. In Phase II, lead optimization andadditional preclinical studies will be performed with selected inhibitors to ascertain their ability to modulate USP4functions and to dampen inflammation in relevant mouse models. The ultimate commercial goal is the developmentof novel small molecule agents that can be used in combination to treat (steroid resistant) asthma.