(572) Therapeutic Efficacy of a Novel Oral NRF2 Activator in a Murine Ulcerative Colitis Model

Introduction/Rationale: Ulcerative colitis (UC) arises from three interconnected pathological processes: impaired epithelial barrier function, persistent mucosal inflammation, and elevated oxidative stress. NRF2 (NF-E2–related factor 2), a transcription factor that serves as a central coordinator of cellular defense programs, orchestrates antioxidant defenses, inhibits inflammatory pathways, and facilitates epithelial regeneration. Beyond its cytoprotective functions, NRF2 activation regulates intestinal immunity and influences UC development. To address the multifactorial drivers of UC, we have developed a novel, potent, and selective oral NRF2 agonist that shows efficacy in a preclinical model of UC.

Methods: MTAI-1025 was evaluated for in vivo efficacy in a 14-day DSS-induced mouse colitis model. Mice received compound (30, 60, or 100 mg/kg, PO, daily from days -1 to 12), vehicle, or a reference anti-IL-12p40 monoclonal antibody (10 mg/kg, IP on days 6 and 9). Inhibition of immune-related signaling was determined in LPS/IFN-g-stimulated monocyte-derived DCs. MoA studies were conducted using HEK293 cells stably transfected with FLAG-NRF2 and HA-KEAP1 (wt or C151) or HEK293 cells stably transfected with split-luciferase tagged Cul3 or NRF2 and KEAP1.

Results: In the DSS model, MTAI-1025 dose-dependently reduced DAI and body weight loss. Treatment also improved mucosal architecture, decreased inflammatory cell infiltration, and lowered pro-inflammatory cytokine levels (IL-1β, IL-6, CXCL1) compared with controls. Dose-dependent activation of the NRF2 transcriptional pathway was confirmed by induction of NQO1 mRNA. MTAI-1025 reduced cytokine secretion in MoDC cells and specifically regulated the dynamics of the NRF2/KEAP1/Cul3 complex at KEAP1 C151.

Conclusion: These results demonstrate that MTAI-1025 effectively attenuates inflammation and exhibits efficacy in an in vivo model of UC, supporting its potential as a first-in-class oral NRF2-targeted therapy for UC.