Ubiquitin pathway inhibitors for treatment of asthma

Asthmaa chronic illness affecting all agesis increasing in prevalenceIn the USAmillion adults andmillion children currently have asthmathe populationAsthmawhich significantly affects the quality of life with no available cureis managed mainly by symptomatic treatments with corticosteroids andagonists whichwhile effectiveexert significant adverse effectsImprovedtargeted therapies are needed for this allergic diseaseGenetic and environmental factorse gallergens and respiratory infectionstrigger and exacerbate asthmaImmune responses differentiate CDT cells into effector T cells that secrete inflammatory cytokinesIn particularasthma is characterized by increases in THand THeffector cells that mediate influx of eosinophils and neutrophilswhich produce the airway inflammation related symptoms of asthmaThussuppression of pro inflammatory cytokines and chemokines is an attractive therapeutic approach to dampen allergic responses in asthmaProtein ubiquitylation is a key regulatory mechanism of innate and adaptive immune systems mediating inflammationNeddfamily Eligasesincluding Itchnegatively regulate inflammatory immune responses by suppressing THand THdifferentiation and cytokine productionGenetic disruption of Itch leads to the development of multi system immune disorders and lung inflammationItch exists in an auto inhibited state with no ligase functionactivation is achieved by binding of proteins such as Ndfipwhich restores its Eligase activityNdfipmice develop asthma like lung inflammation linked to THandTHT cellsand Ndfip protein activates Neddfamily Eligases in cellsattenuating THand THcell functionsFinallySNPs in Ndfipare linked to asthma and atopic dermatitisThusNdfip is a master suppressor of T cell mediated inflammatory responsesThe therapeutic hypothesis of the successful Phase I project was that that small molecule mimics of Ndfipcan be used to selectively activate ubiquitylation cascades to limit THand THcytokine production and to dampen allergic inflammationIn the Phase I project a novel TR FRET based homogeneous Eassay was used to identifyin high throughput screeningsmall molecule mimics of Ndfipthat selectively activated Itch in vitro and in cellsSelected activators induced Treg differentiation of CDT cellsand treatment of Ndfipcells with the Itch activator Psuppressed production of the pro inflammatory cytokine ILIn Phase IIlead optimization and additional preclinical studiesADME PKefficacy in animal modelswill be performed with selected agonists to ascertain their ability to modulate Itch functions and to dampen inflammation in relevant mouse models