A Gut-Restricted Small-Molecule Therapeutic for a Novel Target to Treat Inflammatory Bowel Disease
Abstract
The purpose of this proposal is the creation of an intestinal epithelial targeted small molecule inhibitor of PAI-1 for moderate to severe inflammatory bowel disease patients. The rationale for this molecular target is that PAI-1 is elevated in areas of mucosal injury in patients with both major forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis. Our predictive algorithms supported a driver role for PAI-1 in maintaining dysregulated epithelium and immune activity. Our preclinical work supported this model and further suggested the cellular target of excess PAI-1 was wound associated epithelial (WAE) cells; excess PAI-1 inhibits tPA which is required for WAE cell migration across wound beds. Thus, a program aimed to inhibit PAI-1 would promote tissue repair in IBD. We have designed small molecules to inhibit PAI-1 and target the gut epithelium by oral delivery. This project was designed to choose a lead compound and perform the pre-IND studies for it. We entered this program with a lead compound in hand, CCF104. Our initial studies evaluating toxicity and PK in rodents are supportive of continuing to move forward with this compound into year 2. We also have produced 90 additional analogue compounds to screen for a backup PAI-1inhibitor. We have performed binding assays and we are currently evaluating their activity in an in vitro tPA activity assay. Based on these findings, our goal is to evaluate top candidates based on binding activity for in vivo activity testing using in vivo injury models. This activity we expect will produce at least one backup compound for this program.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2023
- Accession Number
- AD1216538
Entities
People
- Thaddeus S. Stappenbeck