Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor.
The interleukin-12 (IL-12) cytokine induces the differentiation of naive T cells to the T helper cell type 1 (Th1) phenotype and is integral to the pathogenesis of Th1-mediated immunologic 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 severe combined immunodeficiency (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 interferon-gamma (IFN-gamma) 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 immunologic disorders. STA-5326 currently is being evaluated in phase 2 clinical trials in patients with Crohn disease and rheumatoid arthritis.
Wada
Yumiko
Y
Synta Pharmaceuticals Corp, Lexington, MA 02421, USA. ywada@syntapharma.com
Lu
Rongzhen
R
Zhou
Dan
D
Chu
John
J
Przewloka
Teresa
T
Zhang
Shijie
S
Li
Long
L
Wu
Yaming
Y
Qin
June
J
Balasubramanyam
Vishwasenani
V
Barsoum
James
J
Ono
Mitsunori
M
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D003106:Colon / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy; D015536:Down-Regulation / Q000187:drug effects; D000882:Haplorhini; D006801:Humans; D006835:Hydrazones; D007249:Inflammation / Q000188:drug therapy; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000235:genetics; D053759:Interleukin-23 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D021122:Protein Subunits; D011743:Pyrimidines; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*
D006835:Hydrazones; D053759:Interleukin-23; D009025:Morpholines; D021122:Protein Subunits; D011743:Pyrimidines; D014227:Triazines; D018664:Interleukin-12; C504227:apilimod