VPR-254: an inhibitor of ROR-gamma T with potential utility for the treatment of inflammatory bowel disease

Leo R. Fitzpatrick*, Jeff Small, Robert O’Connell, George Talbott, Gordon Alton, Jim Zapf

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Introduction: Retinoic Acid Related Orphan Nuclear Receptor gamma T (RORγT) is a lineage specifying transcription factor for IL-17 expressing cells, which may contribute to the pathogenesis of Inflammatory Bowel Disease (IBD). VPR-254 is a selective in vitro inhibitor of RORγT. Aims: The main goals of our study were twofold: (1) To determine if ex vivo treatment with VPR-254 reduced relevant cytokine (IL-17 and IL-21) secretion from colonic strips of mice with colitis; (2) To determine if treatment of mice with VPR-254 attenuated parameters of colitis, using three murine IBD models. Methods: VPR-254 was evaluated ex vivo in a colonic strip assay, using tissue from mice with Dextran sulfate sodium (DSS)-induced colitis. In vivo, VPR-254 was evaluated for efficacy in DSS, Trintirobenzenesulfonic acid (TNBS) and Anti-CD40 antibody-induced murine models of colitis. Results: VPR-254 reduced the production of key pro-inflammatory cytokines (e.g., IL-17) in ex vivo and in vivo models of colitis. This small molecule inhibitor of RORγT also improved various morphometric and histological parameters associated with three diverse murine models of IBD. Conclusion: Our results support the concept that an inhibitor of ROR-gamma T may have potential utility for the treatment of IBD.

Original languageEnglish
Pages (from-to)499-511
Number of pages13
Issue number2
StatePublished - 1 Apr 2020
Externally publishedYes


  • Colitis
  • Inflammatory bowel disease
  • Mice
  • Rorγt
  • VPR-254


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