Abstract
Abstract Background Our study has revealed that GPRx regulates gut DC migration to local draining lymph node to induce iTreg (Fig 1).1 To fulfil our drive to drug discovery and development for IBD (and other autoimmune diseases) program, we’ve rationally designed small molecule oral GPRx agonists that can induce gut antigen specific iTreg and intended to examine their efficacy utilizing TNBS induced acute IBD model.2-4 Methods C57/BL6 8-10 weeks old female mouse was intrarectally administered with 2,4,6-trinitrobenzene sulfonic acid (TNBS) in 30% ethanol solution through a special catheter to induce colitis, from day 0 to day 4. The tested drug was given via PO, from day 0 to day 4. The experiment ended on day 5. DAI (disease activity index) on weight loss, diarrhea, and rectal bleeding, was recorded daily, to determine disease severity. Colon was taken at the end of experiment for measurement and photography. Results A series of compounds have been tested using this in vivo TNBS induced acute IBD mouse model and some of them have shown excellent activity (Fig 2). Conclusion With this new MOA and first-in-class approach using small molecule oral GPRx agonists for Treg cell therapy, we could develop a different treatment for IBD (and other autoimmune diseases in general) patients than JAK inhibition or a4b7 inhibition or S1P1 activation, etc. The outstanding efficacy data described here together with their safety profile and acute/sub-acute toxicity results have provided us the confidence to a successful IND late-2025.
Published Version
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