2. Academic Validation
  3. Orally Bioavailable BRD4 BD1 Inhibitor ZL0516 Effectively Suppresses Colonic Inflammation in Animal Models of Inflammatory Bowel Disease

Orally Bioavailable BRD4 BD1 Inhibitor ZL0516 Effectively Suppresses Colonic Inflammation in Animal Models of Inflammatory Bowel Disease

  • ACS Pharmacol Transl Sci. 2025 Apr 1;8(4):1152-1167. doi: 10.1021/acsptsci.5c00068.
Zonghui Ma 1,  Steven McAninch 2,  Zhiqing Liu 1,  Cun Zhang 1,  Haiying Chen 1,  Jing He 3,  Wenjing Yang 4,  Ronaldo P Panganiban 5,  Yingzi Cong 4,  Gregory Yochum 6,  Allan R Brasier 7,  Irina V Pinchuk 2,  Bing Tian 8,  Jia Zhou 1
Affiliations

Affiliations

  • 1 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States.
  • 2 Department of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, United States.
  • 3 Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States.
  • 4 Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
  • 5 Department of Medicine, Penn State College of Medicine, Hershey, Pennsylvania 17033, United States.
  • 6 Division of Colon and Rectal Surgery, Department of Surgery, and Department of Biochemistry and Molecular Biology, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, United States.
  • 7 Institute for Clinical and Translational Research (ICTR) School of Medicine and Public Health, 4248 Health Sciences Learning Center, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.
  • 8 Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States.
PMID: 40242579 DOI: 10.1021/acsptsci.5c00068
Abstract

Inflammatory bowel disease (IBD), a chronic, progressive, and recurrent gastrointestinal inflammatory disorder, poses a significant threat to global health and exerts an adverse effect on the quality of life. Currently, there is a lack of effective therapies for IBD. Developing novel targeted therapies for IBD, particularly orally effective therapeutics, is a vital need for IBD patients. Herein, we first demonstrate that BRD4/NF-κB signaling is aberrantly activated in the colons of human IBD biopsy samples compared to that of normal healthy controls. ZL0516, a potent, selective, and orally bioavailable BRD4 BD1 Inhibitor, significantly inhibits the TNFα- and LPS-induced expression of inflammatory cytokines in human colonic epithelial cells (HCECs) and peripheral blood mononuclear cells (PBMCs) with low cytotoxicity. Intriguingly, when administered in a preventive mode, ZL0516 significantly blocks dextran sulfate sodium (DSS)-induced murine colitis. When used in a therapeutic mode, ZL0516 effectively suppresses colonic inflammation in several IBD-relevant animal models: DSS-, oxazolone (OXA)-, and flagellin (Cbir1) T cell-induced chronic murine colitis models of IBD. ZL0516 suppresses IBD inflammatory responses in vitro and in vivo by blocking the activation of the BRD4/NF-κB signaling pathway. Also, we found that RVX208, a selective BRD4 BD2 Inhibitor in Phase III clinical development, only displayed marginal effects in these IBD animal models. Collectively, our results demonstrate that specific BRD4 BD1 inhibition is a novel therapeutic strategy for IBD-associated colonic inflammation, and orally effective inhibitor ZL0516 is a promising candidate for the development of a novel therapeutic regimen against IBD.

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