Ameliorative effect of a quinazoline-based bromodomain inhibitor, CN210, on experimentally-induced Crohn's disease-like murine ileitis via inhibition of inflammatory cytokine expression

Abstract

Inhibitors of bromodomain and extra-terminal motif proteins ("BET inhibitors") are emerging epigenetic therapeutics that exert their effects by suppressing the expression of genes that drive cancer and inflammation. The present study examined the anti-inflammatory effects of a quinazoline-based BET inhibitor, CN210, which also inhibits bromodomains of two paralogous histone acetyltransferases (HATs), such as cAMP-responsive element binding protein-binding protein (CBP) and p300. To assess its effectiveness against inflammatory bowel disease (IBD), CN210 was tested in an experimentally-induced murine Crohns disease (CD)-like ileitis model. Ileitis was induced in mice by subcutaneous administration of indomethacin and CN210 was given orally 30 min before and 24 h after the indomethacin administration. Whilst indomethacin produced severe ileitis accompanied by an increase in ileal mucosal myeloperoxidase (MPO) activity, administration of CN210 reduced the severity of ileitis in a dose-dependent manner and suppressed the MPO activity. Similarly, upregulation of inflammatory cytokines was observed in ileitis mucosa after indomethacin injection but this response was significantly attenuated by CN210 administration. To further characterize the effects of CN210 on inflammatory pathways, monocyte/macrophage-like cell line RAW264 treated with lipopolysaccharide (LPS) was exposed to CN210. CN210 significantly attenuated the expression of inflammatory cytokines and reversed the activation of NF-{kappa}B and MAP kinases induced by LPS. These findings suggest that CN210 ameliorates indomethacin-induced ileitis due at least in part to the inhibition of inflammatory cytokine expression via attenuation of NF-{kappa}B and MAP kinase pathways, thus representing a new mode of therapy for CD.