First-in-class small molecule therapeutics to enhance GUT barrier function in inflammatory bowel disease PA-20-260, R43 phase i sbir PI: frederick m. Ausubel project summary inflammatory bowel disease…

First-in-class small molecule therapeutics to enhance GUT barrier function in inflammatory bowel disease PA-20-260, R43 phase i sbir PI: frederick m. Ausubel project summary inflammatory bowel disease (IBD), which affects approximately to 3 million americans, is characterized by chronic relapsing inflammation and barrier dysfunction, manifested as enhanced permeability of the intestinal epithelium caused by a breakdown of tight junction proteins between cells. Because FDA-approved IBD therapeutics target inflammation rather than barrier dysfunction, there is a current need for an orally available, non-toxic, non-immunosuppressive IBD therapeutic that directly enhances barrier function and blocks progression to more severe forms of IBD. Artus therapeutics is developing IBD therapeutics inspired by the natural microbiome compound urolithin a (uroa). Uroa exhibits anti-inflammatory activity and a highly favorable toxicity profile in rodents and humans, but its lack of stability at low PH is a major impediment for its further development. Artus therapeutics has synthesized a urolithin analog, artx-2, that is significantly more acid stable and more resistant to hydrolysis by digestive enzymes than uroa. Published and preliminary data show that oral administration of artx-2 dramatically mitigates the symptoms of dextran sodium sulphate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (tnbs) induced ulcerative colitis in mice. Further, artx-2 up-regulates tight junction proteins (tjps) including CLAUDIN4 and occludin in GUT epithelium as well as blocks LPS-induced inflammatory cytokines in bone marrow derived macrophages (bmdms). Genetic analysis in mice shows that the bioactivity of artx-2 is dependent upon the aryl hydrocarbon receptor (AHR) and the nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2). Based on these observations, IT was concluded artx-2 mitigates IBD through activation of AHR-dependent pathways at two distinct levels: by (i) preserving and/or enhancing GUT barrier function and (II) reducing systemic and acute inflammation by downregulating inflammatory cytokines in immune cells. Based on the promising data with artx-2, 44 more artx-2 analogs have been synthesized and preliminary data show that some of these analogs appear to be more potent than artx-2 in blocking the production of inflammatory cytokines in bmdms. In this sbir phase i application, we propose lead optimization of artx-2. In aim 1, we will compare artx-2 and 44 artx-2 analogs with respect to: 1) upregulation of tjps: 2) decrease in epithelial permeability; and 3) downregulation of cytokines. Up to 10 analogs that are equally or more potent than artx-2 will be further tested for their efficacy in dose-response assays. In aim 2, we will carry out efficacy studies in the mouse tnbs chemically-induced model of ulcerative coliits for the top 5 prioritized compounds from aim 1. For the 3 most efficacious compounds in the mouse tnbs model, we will further test for efficacy in the mouse DSS chemically-induced model of ulcerative colitis. The overall goal of the proposed project is to identify 2-3 artx-2 analogs that are equally or more potent that artx-2 for advancement to a phase II project where further PK and toxicity testing will allow US to identify a single compound that will be advanced into IND-enabling studies. Artus therapeutics PA-20-260 / PI: frederick m. Ausubel project summary - page 1 of 1