BET inhibitors(The University of Nottingham)

The bromodomain and extra-terminal domain (BET) protein family is a class of epigenetic reader proteins that recognize N-acetylated lysine residues in histone tails, playing a crucial role in gene expression and cell transcription. Selective inhibition of bromodomain-containing proteins (BRDs) disrupts transcription in key oncogenes. Over the past decade there has been considerable interest in developing small molecule BET inhibitors for the treatment of hematological malignancies and solid tumors. Herein, we report the development of a triazinoindole scaffold capable of the inhibition of bromodomain-containing protein 4 (BRD4), with either dimethylisoxazole or dimethyltriazole substituents acting as chemomimetics of the N-acetylated lysine residues. Derivatization of the parent scaffold afforded the lead compound, which displays low nanomolar affinity toward BRD4-BD1 with a favorable physicochemical and in vitro stability profile.

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.