KB-0118, A novel BET bromodomain inhibitor, suppresses Th17-mediated inflammation in inflammatory bowel disease

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Authors: Yeo-Jin Jeong ; Yeon-Su Ok ; Gi-Nam Kwon ; Min-Young Kim ; Jin Hong Chun ; Sukmo Kang ; Haemi Yang ; Minhee Son ; In-Hyun Lee ; Gi-Cheon Kim ; Ho-Keun Kwon

MeSH: Animals ; Anti-Inflammatory Agents* / pharmacology ; Bromodomain Containing Proteins ; Cell Cycle Proteins / antagonists & inhibitors ; Cell Differentiation / drug effects ; Colitis / chemically induced ; Colitis / drug therapy ; Colitis / immunology ; Colitis / pathology ; Cytokines / metabolism ; Dextran Sulfate ; Disease Models, Animal ; Humans ; Inflammation Mediators / metabolism ; Inflammation* / drug therapy ; Inflammatory Bowel Diseases* / drug therapy ; Inflammatory Bowel Diseases* / immunology ; Inflammatory Bowel Diseases* / metabolism ; Inflammatory Bowel Diseases* / pathology ; Male ; Mice ; Mice, Inbred C57BL ; Nuclear Proteins / antagonists & inhibitors ; Nuclear Proteins / metabolism ; Th17 Cells* / drug effects ; Th17 Cells* / immunology ; Th17 Cells* / metabolism ; Transcription Factors* / antagonists & inhibitors ; Transcription Factors* / metabolism

Keywords: BET Bromodomain inhibitor ; Inflammatory bowel disease ; KB-0118 ; T helper 17 cells

Abstract: Inflammatory bowel disease (IBD) presents complex pathologies and remains challenging to treat, highlighting the urgent need for innovative therapeutics. This study evaluates KB-0118, a novel BET bromodomain inhibitor targeting BRD4, for its immunomodulatory effects in IBD. KB-0118 effectively inhibited pro-inflammatory cytokines, including TNF, IL-1β, and IL-23a, and selectively suppressed Th17 cell differentiation, a critical driver of IBD pathology. In both DSS-induced and T cell-mediated colitis models, KB-0118 significantly reduced disease severity, preserved colon structure, and lowered IL-17 expression. Mechanistic studies suggest KB-0118's modulation of Th17-driven inflammation occurs through epigenetic suppression of BRD4, confirmed by transcriptomic analysis showing downregulation of STAT3 and BRD4 target genes. Compared to standard BET inhibitors like JQ1 and MS402, KB-0118 exhibited enhanced efficacy in restoring immune balance in IBD, positioning it as a promising therapeutic candidate for chronic inflammatory diseases. Further investigation into KB-0118's specificity and long-term effects will be essential to clarify its full clinical potential.