Senior Research Associate Equillium Bio, United States
Disclosure(s):
Mary Casis, MA: No relevant disclosure to display
Introduction/Rationale: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that integrates environmental signals to regulate intestinal immune homeostasis and epithelial barrier integrity. In inflammatory bowel disease, AhR modulators have shown clinical benefit partly through induction of IL-22, which enhances epithelial repair and barrier function. However, differences in the epithelial-directed activity and functional outcomes of AhR-targeting agents remain poorly defined. EQ504 is a novel, potent small-molecule AhR agonist being developed for the treatment of ulcerative colitis to promote mucosal healing.
Methods: AhR activation was evaluated in HepG2 cells using the EROD assay. Epithelial repair was assessed in T84 human intestinal epithelial cells using in vitro scratch wound healing assays. Expression of epithelial barrier-related genes was quantified in T84 cells at matched compound concentrations. Ongoing studies include transepithelial electrical resistance measurements and human intestinal organoid models.
Results: EQ504 induced robust, dose-dependent AhR activation, and was ~10-fold more potent than the clinically validated AhR agonist obefazimod in the EROD assay. Functionally, EQ504 significantly accelerated epithelial wound closure in scratch assays, whereas obefazimod showed minimal or no effect under equivalent conditions. At matched concentrations, EQ504 increased expression of the IL-22 receptor subunit IL22RA and reduced expression of the pore-forming tight junction protein claudin-2 (CLDN2), consistent with enhanced epithelial repair, which were not observed with obefazimod.
Conclusion: These findings demonstrate that EQ504 is a potent AhR agonist with superior epithelial repair and barrier-stabilizing activity compared to obefazimod. The ability of EQ504 to promote IL-22 responsiveness while reducing CLDN2 expression highlights functional differentiation among AhR-targeting therapies and supports its development as a promising treatment for inflammatory mucosal diseases.
