Ubiquitin E3 ligase activators for treatment of psoriasis

Psoriasis is a chronicuncurable multisystem inflammatory disease affecting skin and joints and leading to numerous complicationsSymptomatic relief is availablebut treatmentsincluding biologicalsare compromised by safety and other issuessuggesting a need for improved therapiesPsoriasis is driven by immune cell derived proinflammatory cytokines that cause uncontrolled keratinocyte proliferationthese cytokines can be induced by TNFand TNF blocking antibodies such as adalimumab are approved for chronic plaque psoriasisIn additionT helperThcells produce ILA and ILFwhich also activate keratinocyte proliferationAccordinglythe anti ILA antibody secukinumab is approved for psoriasisThussuppression of THdifferentiation and or ILsignaling is a validated therapeutic approach for treating the underlying causes of psoriasisThe ubiquitin proteasome pathway is a primary regulator of immune functionthe Neddfamily Eligase Itchwhich negatively regulates inflammatory responsesis a validated target for inflammationGenetic ablation of Itch leads to multisystem immune disordersThe ligase is normally autoinhibited but is activated by the adapter protein NdfipNdfipmice develop inflammatory disease similarly to ItchmiceRecentlyDrVenuprasad Poojary s laboratory discovered that Itch causes proteasomal degradation of the lineage specific transcription factor RORTthereby suppressing Thdifferentiation and ILproductionItchmice develop spontaneous colitis and exhibit elevated ILlevelsThusItch is a master negative regulator of inflammatory responses and its activation should provide therapeutic benefitProgenra recently discovered small molecule Itch activatorsand subsequent lead optimization has identified distinct chemical scaffoldsPand Pthat selectively activate Itch and impair cytokine production by T cellsMoreoverthey suppress ILmRNAlevels in ThcellsIt is proposed here to develop small molecule Itch activators as oral agents to limit THdifferentiation and cytokine productionultimately dampening the inflammatory responses in in vivo models of psoriasis and potentially having utility to treat severe to moderate psoriasisIn Phase Ithe effect of selective Itch activators on Thcell differentiationILproductionand RORT protein levels will be determinedand candidate activators will be evaluated for pharmacokinetics and oral bioavailabilityThe Imiquimod induced murine psoriasis model will be employed to determine in vivo efficacyIn Phase IIlead development and preclinical evaluation will continue using clinically relevant animal modelsA successful project will lead to novel small molecule agents that can be used alone or in combination to treat psoriasis and other inflammatory diseases Psoriasis is driven by immune cell derived proinflammatory cytokines that cause uncontrolled keratinocyte proliferationimmune functionin turnis regulated by the ubiquitin proteasome pathway for protein degradation and homeostasisIt is proposed to develop a novel treatment for psoriasis by activating the ubiquitin pathway enzyme Itchwhich has been shown to be responsible for shutting off the cytokine release that triggers the inflammatory disease