Modulating immune toxicity in ulcerative colitis using a small molecule RAB27A inhibitor.

BACKGROUND: Recent evidence has shown that ulcerative colitis patients with increased neutrophil biomarkers are linked to complicated disease and refractory response. In the pathology of colitis, neutrophils are recruited to the colon and yield acute damage via reactive oxygen species (ROS), degranulation, and neutrophil extracellular traps (NETosis). RAB27A is a regulator of intracellular membrane trafficking and has been shown to play a role in neutrophil activation by enabling the increased release of proteolytic granules and ROS. Studies have shown significant upregulation of RAB27A expression in biopsies of moderate and severe ulcerative colitis patients, while preclinical studies genetically deleting RAB27A in ulcerative colitis models have shown improved outcomes. METHODS: To evaluate the impact of RAB27A inhibition in ulcerative colitis and lower activated neutrophil toxicity in the disease, we developed IMYX-3, a first-in-class small molecule oral inhibitor of RAB27A activity and applied it to the study of diseased neutrophils and models. RESULTS: IMYX-3 lowers neutrophil ROS, degranulation, NETosis, and cytokine secretion. Preclinical efficacy was demonstrated in dextran sulfate sodium and Il10-/- mouse models, in which IMYX-3 treatment led to improved colon length, reduced systemic inflammation, lower levels of activated neutrophil function, and comparable disease outcomes compared with standard-of-care control mice. In vitro toxicity profiling as well as pharmacokinetic and toxicology studies in rodents and canines showed a favorable drug profile, with no significant adverse events observed at doses up to 30 times the predicted therapeutic range. CONCLUSION: IMYX-3 effectively inhibits RAB27A activation in neutrophils, yielding improved outcomes in preclinical disease models with no major safety concerns.