Small-molecule inhibition of mechanisms shared across pathogenic cells in systemic lupus erythematosus

Systemic lupus erythematosusSLEis a potentially fatalmultifactorial chronic autoimmune diseaseThe disease profile of SLE is highly diverseand is affected by environmental contributions as well as varied genetic factorsDespite the heterogeneity in disease severity and pathogenic mechanisms in SLErecent studies have indicated that the most robust transcriptional biomarkers of disease progression are signatures of increased B cell activation differentiation and increased type I interferon productionTherapies targeting these central markers of disease pathogenicity are particularly promising research areasImportantlypathways mediating B cell activationB cell differentiationand type I interferon release share a common componentTumor necrosis factor receptorTNFRassociated factorTRAFDefective negative regulation of TRAFsignaling is seen in SLEand the role of TRAFas a regulator central to the major cellular processes in SLE pathogenicity highlights TRAFas a critical therapeutic targetProgenra proposes to validate and perform a high throughput screening campaign to identify novel and selective small molecule TRAFinhibitorsProgenra s diverse library ofsmall molecules and established experience in discovery of ubiquitin ligase inhibitors provides a strong developmental platform to identify these moleculesCellular proof of concept assays will be conducted on selected hits to evaluate their effect TRAFdependent signaling pathwaysincluding type I interferon secretionTLRmediated NF B activationand expression of the transcriptional regulator of type I interferon factorIFNSmall molecule TRAFinhibitors will decrease type I interferon signaling and B cell activationcellular processes related to SLE pathogenesisThusTRAFinhibition allows selective inhibition of inflammatory signaling mechanisms specific to the disease progression of SLE Systemic lupus erythematosusSLEis characterized by increased B cell activation differentiation and increased type I interferon productionTherapies targeting these mechanisms will be developed by discovering inhibitors of TRAFa ubiquitin pathway enzyme that is linked to bothsuch inhibitors will facilitate selective inhibition of inflammatory signaling mechanisms specific to the disease progression of SLE