# First-in-class small molecule therapeutics to enhance gut barrier function in inflammatory bowel disease

> **NIH NIH R43** · ARTUS THERAPEUTICS INC · 2021 · $251,191

## Abstract

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 effi...

## Key facts

- **NIH application ID:** 10251430
- **Project number:** 1R43DK127754-01A1
- **Recipient organization:** ARTUS THERAPEUTICS INC
- **Principal Investigator:** Frederick M Ausubel
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $251,191
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10251430

## Citation

> US National Institutes of Health, RePORTER application 10251430, First-in-class small molecule therapeutics to enhance gut barrier function in inflammatory bowel disease (1R43DK127754-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10251430. Licensed CC0.

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