Targeting IRF5 with selective covalent oral small molecules attenuates Type I IFN and pro-inflammatory cytokine secretion in human PBMCs and in mice 2309520

Abstract

Abstract Introduction Interferon regulatory factor 5 (IRF5) is an undrugged transcription factor strongly associated with autoimmune diseases including systemic lupus erythematosus (SLE), Sjögren’s syndrome, and rheumatoid arthritis. In those diseases IRF5 is dysregulated, causing proinflammatory cytokine and Type I interferon (IFN) secretion, exacerbating inflammation. Knockout of IRF5 suggests its loss protects from inflammatory arthritis, colitis, and SLE, positioning IRF5 as a highly attractive target for dampening pathological inflammation. This study reports the discovery of IRF5 inhibitors to control autoimmune disease. Methods A novel, cell-based DNA-encoded library platform–OmniDEL–was used to screen for IRF5 inhibitors. Compounds were characterized in acutely stimulated THP-1 cells, human peripheral blood mononuclear cells (PBMCs), human monocytes, and mouse models. A TLR7/8 agonist, R848, was used to stimulate cells and trigger secretion of Type I IFNs and cytokines, which were quantitated by ELISA. High content imaging assessed IRF5 nuclear translocation. Results OmniDEL produced IRF5 hits from cell lysates. Off-DNA initial hits confirmed covalent engagement by mass spectrometry, exhibited selectivity for IRF5 vs family members, and inhibited PBMC cytokine responses. In a dose dependent manner, initial hits and improved compounds inhibited IRF5 nuclear translocation in monocytes, and inhibited cytokine secretion –including IL-6, TNFα, IL-12, and IL-1β–in monocytes and PBMCs. Upon R848 stimulation, compelling inhibition was observed in normal mice and in mice with a humanized immune system. No toxicity was observed in mice dosed twice daily at high levels for up to 7 days. Conclusion This study describes the discovery and proof-of-concept of the first covalent IRF5 small molecule inhibitors. These data support advancement towards DC nomination and clinical development with the goal of developing a best-in-class oral therapy for the treatment of autoimmune and other serious inflammatory diseases. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)