Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease.

Authors:
William C Reisdorf
William C Reisdorf
a Computational Biology
College Park | United States
Qing Xie
Qing Xie
Ruijin Hospital
China
Xin Zeng
Xin Zeng
Sichuan University
China
Wensheng Xie
Wensheng Xie
Collegeville
United States
Neetu Rajpal
Neetu Rajpal
Metabolic Drug Discovery
Bao Hoang
Bao Hoang
UCLA School of Medicine
United States
Mark E Burgert
Mark E Burgert
Hospital of the University of Pennsylvania
United States
Vinod Kumar
Vinod Kumar
All India Institute of Medical Sciences
India

PLoS One 2019 19;14(4):e0215033. Epub 2019 Apr 19.

Computational Biology, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.

Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1β in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215033PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474586PMC
April 2019
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