Efficacy of a novel oral, potent, and highly selective PKCt inhibitor in the SCID T-cell transfer colitis model

---

Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B854
Abstract ID: 4576

Presenting Author:
Jamie L Harden , Director of Research at Evommune

Abstract:

Protein kinase C family theta isoform (PKCt) is a key kinase downstream of T-cell receptor (TCR) and CD28 co-signaling in T-cells, leading to T-cell activation and production of effector cytokines. As T-cells are key pathogenic cells in a multitude of chronic inflammatory diseases, inhibition of PKCt with an oral small molecule may provide a novel mechanism to treat chronic inflammatory diseases, such as colitis. In this study, we evaluated the efficacy of two orally bioavailable, potent, and highly selective PKCt inhibitors in the severe-combined-immunodeficient (SCID) T-cell transfer colitis model; this model is considered the most relevant to human inflammatory bowel disease (IBD), and displays characteristics of both Crohn’s disease (CD) and ulcerative colitis (UC). PKCt inhibition resulted in a dose-dependent prevention of colitis symptoms, including maintenance of body weight and stool score, with efficacy similar to an anti-IL-12 monoclonal antibody. Histological assessment and tissue cytokine and chemokine protein quantification of the colon were also performed. These data suggest that an oral PKCt inhibitor may have utility in the treatment of IBD, and other chronic inflammatory diseases driven by pathogenic T-cell activation.