BACKGROUND
Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is characterized by chronic, recurrent mucosal inflammation of the digestive tract. Current treatments come with considerable side effects, are very expensive, and only work in ~50% of patients. Despite recent advances, IBD continues to rise in incidence, burdening our health care system, thereby emphasizing the need to find more effective therapies to treat these diseases.
TECHNOLOGY
Inventors at the University of Toronto have identified a novel gene encoding an “enzyme X” with no ascribed function as promoting IBD in mouse models (unpublished work). Mice deficient in this enzyme, or inhibiting the enzyme with an orally-delivered small molecule inhibitor (i.e. compound Z), prevents IBD using multiple mouse models of IBD. Importantly, genome-wide association studies (GWAS) have linked this gene to IBD in humans emphasizing the relevance of this work to human disease.
COMPETITIVE ADVANTAGE
- Novel drug-able target that has been validated by initial drug screens
- Inhibitors against this new target for IBD
APPLICATIONS
- Treatment of IBD
INTELLECTUAL PROPERTY
- Provision patent filed (2022)
PROJECT STATUS
A novel gene product, “Enzyme X”, has been shown to play a key role during IBD induction in mice (Figure 1). Proof-of-concept studies have suggested that inhibition of this protein by a small molecule inhibitor, Compound Z, protects against developing IBD in mice models (Figure 2). A screen of 70,000 small molecules was used to identify more specific inhibitors for Enzyme X. A SAR program is currently being conducted.
Figure 1. Enzyme X implication in IBD. Two measures, colon length and caecum weight, are one of many assays that were used to measure DSS-induced colitis in these mice. Mice containing Enzyme X (+/+) display a reduction in colon length and weight compared to knockouts (-/-) upon induction of colitis with DSS; implicating Enzyme X participation in IBD onset and also its potential as a therapeutic target.
Figure 2. Compound Z protects against DSS-induced colitis. Mice containing Enzyme X (+/+) display a reduction in colon length compared to knockouts (-/-), showing that Enzyme X is involved in this disease. Inhibition of Enzyme X by Compound Z (+/+ +Z) results in significant retention of colon length, demonstrating potential as a therapeutic.
TEAM
The team comprises several experts in the fields of IBD (Drs. Ken Croitoru and Alberto Martin), an expert in crystallography and drug development (Dr. Frank Sicheri), as well as other collaborators to enable this research program. Dr. Martin is leading the team, coordinating activities and overseeing the research agenda.
