A quinazoline-based bromodomain inhibitor, CN210, ameliorates indomethacin-induced ileitis in mice by inhibiting inflammatory cytokine expression.

Abstract

Inhibitors of bromodomain and extra-terminal motif (BET) proteins are emerging epigenetic therapeutics that suppress gene expressions that drive cancer and inflammation. The present study examined anti-inflammatory effects of a quinazoline-based BET inhibitor, CN210, in a murine ileitis model. CN210 was given orally 30 min before and 24 h after a subcutaneous administration of indomethacin. Macroscopic and histological evidences of ileitis, mucosal myeloperoxidase (MPO) activity and cytokine expressions were evaluated 48 h after the indomethacin administration. To further characterize the anti-inflammatory pathways modulated by CN210, its effects on RAW264 cells treated with lipopolysaccharide (LPS) were investigated. Competitive ligand binding and docking studies of CN210 to CREB-binding protein (CBP) and p300 were also performed. Oral administration of CN210 significantly reduced the severity of ileitis, normalized both proinflammatory MPO activity and concomitant cytokine expressions induced by indomethacin administration. Furthermore, CN210 attenuated the expression of cytokines and reversed the activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPK) induced by LPS. Competitive ligand binding assays showed that CN210 bound to the bromodomains of two paralogous histone acetyltransferases, CBP and p300, in addition to the bromodomains of BET proteins. Docking studies of CN210 to the bromodomains of CBP and p300 showed a similarity to the binding mode of SGC-CBP30, a specific CBP/p300 inhibitor. CN210 ameliorates indomethacin-induced ileitis by inhibiting the expression of inflammatory cytokines through the attenuation of NF-κB and MAPK pathways. CN210 thus represents a new mode of therapy for non-steroidal anti-inflammatory drug-induced ileitis and inflammatory bowel disease.

• Authors: Takehisa Noguchi, Kyosuke Hidaka, Satsuki Kobayashi, Kenjiro Matsumoto, Makoto Yoshioka, Xin Hu, David J Maloney, Shyh-Ming Yang, Shinichi Kato
• Journal: Drug development research (Drug Dev Res) Vol. 82 Issue 8 Pg. 1235-1246 (12 2021) ISSN: 1098-2299 [Electronic] United States
• PMID: 34075610 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Wiley Periodicals LLC.

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Membrane Proteins
• NF-kappa B
• Pag1 protein, mouse
• Phosphoproteins
• Proteins
• Quinazolines
• bromodomain and extra-terminal domain protein, human
• Peroxidase
• E1A-Associated p300 Protein
• Ep300 protein, mouse
• Indomethacin

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cytokines (antagonists & inhibitors, biosynthesis)
• E1A-Associated p300 Protein (metabolism)
• Ileitis (chemically induced, drug therapy)
• Indomethacin (adverse effects)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (physiology)
• Peroxidase (metabolism)
• Phosphoproteins (metabolism)
• Proteins (antagonists & inhibitors)
• Quinazolines (pharmacology)
• RAW 264.7 Cells