Genomic-based high throughput screening and identification of small molecule inhibitors targeting IFN α signaling pathways (131.17)

Abstract

Abstract Multiple lines of evidence suggest that inhibition of Type I Interferons (IFNs), including IFN(, may provide a therapeutic benefit in treating a number of autoimmune diseases such as Systemic Lupus Erythematosus (SLE). Herein, we describe the generation and use of AvalonRx-HITS®, a proprietary genomic based high-throughput screen (HTS), followed by immunological assays in primary human cells to identify inhibitors of the IFN( pathway. In the HTS step, THP1 cells were stimulated with IFN( and 268 defined small molecule inhibitors targeting 41 different intracellular signaling pathways were screened for their ability to block a specific IFN(-evoked gene signature. Four classes of compounds emerged from the HTS: NF-(B, JAK/STAT, Ubiquitin/Proteasome and HDAC inhibitors. In secondary assays, these compounds blocked both IFN(-induced human monocyte activation and differentiation into dendritic cells, and IFNs-associated gene signature induced by SLE serum in human monocytes. In addition to their dose-dependent anti-inflammatory effects, inhibitors targeting NF- (B or JAK/STAT signaling did not modulate IFN( anti-viral effects in an in vitro HSV-1 replication assay. In summary, we have developed a novel and robust platform using genomic, immunological and viral assays that may lead to the identification of small molecule inhibitors for the treatment of IFN(-associated autoimmune disorders.