{
  "abstract": "Objectives Dysregulated IRF5 activity drives type I interferon, pathogenic cytokine production, and B cell activation and differentiation downstream of TLR7/8/9 signaling, contributing to systemic lupus erythematosus (SLE) pathogenesis. Despite its genetic and pre-clinical validation, IRF5 has remained challenging to drug due to the lack of a traditional active site. We report preclinical data on novel, potent small molecule IRF5 inhibitors demonstrating robust activity across translational in vitro and in vivo systems, highlighting their potential as a breakthrough therapy for SLE.Methods IRF5 inhibitors were profiled in primary human immune cells and whole blood stimulated with TLR agonists or RNA-containing immune complexes to assess cytokine production. Whole blood assays benchmarked activity against inhibitors of relevant alternative pathways such as Tyk2 and IRAK4. Purified B cells were analyzed for cytokine production and plasmablast differentiation. PBMCs from SLE patients were also tested to evaluate disease-relevant target engagement. In vivo activity was examined in humanized NOG-EXL mice following oral dosing of an IRF5 inhibitor and TLR agonist challenge, with cytokines measured in serum and transcriptional changes assessed in whole blood and spleen using qPCR.Results IRF5 inhibitors achieved potent, dose-dependent suppression of cytokine release in multiple human immune cell types. In whole blood, compounds equaled or surpassed benchmark inhibitors in reducing inflammatory cytokines. In B cells, IRF5 inhibition not only blocked cytokine secretion but also prevented plasmablast differentiation, disrupting a key pathogenic pathway in SLE. IRF5 inhibition in SLE PBMCs exhibited strong, dose-dependent cytokine suppression with enhanced potency compared to competitor compounds. In vivo, oral dosing resulted in dose-dependent cytokine blockade and marked downregulation of IRF5-driven inflammatory transcripts, confirming pathway-level modulation in this model.Conclusions These data establish selective IRF5 inhibition as a novel, compelling strategy to shut down potential drivers of autoimmune inflammation. Our inhibitors demonstrate broad activity across relevant human assay systems, enhanced potency compared to competitor compounds, and robust in vivo effects with relevant transcriptional pathway suppression. These findings provide compelling support for advancing IRF5 inhibitors toward clinical development as a transformative therapy for SLE and other IRF5-associated autoimmune diseases.",
  "authors": [
    {
      "affiliations": [
        "HoSpot Therapeutics, Boston, USA"
      ],
      "name": "Nuruddeen Lewis"
    },
    {
      "affiliations": [
        "HoSpot Therapeutics, Boston, USA"
      ],
      "name": "Guohua Zhao"
    },
    {
      "affiliations": [
        "HoSpot Therapeutics, Boston, USA"
      ],
      "name": "Mark Weir"
    },
    {
      "affiliations": [
        "HoSpot Therapeutics, Boston, USA"
      ],
      "name": "Kathleen Smith"
    },
    {
      "affiliations": [
        "HoSpot Therapeutics, Boston, USA"
      ],
      "name": "Christophe Lamarque"
    },
    {
      "affiliations": [
        "HoSpot Therapeutics, Boston, USA"
      ],
      "name": "Huadong Sun"
    },
    {
      "affiliations": [
        "HoSpot Therapeutics, Boston, USA"
      ],
      "name": "Geraldine Harriman"
    },
    {
      "affiliations": [
        "HoSpot Therapeutics, Boston, USA"
      ],
      "name": "Joseph Wahle"
    }
  ],
  "title": "PO:11:292 Preclinical evaluation of IRF5 small molecule inhibitors with potent activity in lupus-relevant systems",
  "uid": "6961b653-8ad8-524d-a4d4-34f304d59c8c"
}