Submitted April 25, 2006
Accepted August 30, 2006
Selective abrogation of Th1 response by STA-5326, a potent
IL-12/IL-23 inhibitor
Yumiko Wada*, Rongzhen Lu, Dan Zhou, John Chu, Teresa Przewloka, Shijie Zhang, Long Li, Yaming Wu, June Qin, Vishwasenani Balasubramanyam, James Barsoum, and Mitsunori Ono
Synta Pharmaceuticals Corp., Lexington, MA
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
* Corresponding author; email: ywada{at}syntapharma.com.
The IL-12 cytokine induces the differentiation of naive T cells to the Th1 phenotype and is integral to the pathogenesis of Th1-mediated immunological disorders. A more recently discovered IL-12 family member, IL-23, shares the p40 protein subunit with IL-12 and plays a critical role in the generation of effector memory T cells and IL-17 producing T cells. We introduce a novel compound, STA-5326, that down-regulates both IL-12 p35 and IL-12/IL-23 p40 at the transcriptional level, and inhibits the production of both IL-12 and IL-23 cytokines. Oral administration of STA-5326 led to a suppression of the Th1 but not Th2 immune response in mice. In vivo studies using a CD4+CD45Rbhigh T cell transfer SCID mouse inflammatory bowel disease model demonstrated that oral administration of STA-5326 markedly reduced inflammatory histopathologic changes in the colon. A striking decrease in IFN-
production was observed in ex vivo culture of lamina propria cells harvested from animals treated with STA-5326, indicating a down-regulation of the Th1 response by STA 5326. These results suggest that STA-5326 has potential for use in the treatment of Th1-related autoimmune or immunological disorders. STA-5326 currently is being evaluated in phase 2 clinical trials in Crohn's disease and rheumatoid arthritis patients.
