Dihydroorotate dehydrogenase (DHODH) is a key enzyme involved in pyrimidine biosynthesis. DHODH is a known target for the treatment of autoimmune diseases. 4SC-101 is a novel immunosuppressive drug that inhibits DHODH. A goal of our study was to examine the in vitro effects of 4SC-101 on IL-17 production by mononuclear cells. In addition, we evaluated the efficacy of 4SC-101 against acute TNBS (2,4,6-tritrobenzene sulfonic acid) and chronic dextran sodium sulfate (DSS)-induced colitis in mice.
Peripheral blood mononuclear cells (PBMCs) from healthy human donors were used to evaluate cellular proliferation and cytokine (IL-17, TNF-α) production. The oral effects of 4SC-101 (100 or 200 mg/kg) were examined following induction of chronic colitis by the administration of 3% DSS (4 cycles) to Balb/c mice. Morphometric and histological indices of colitis were evaluated as indicators of drug efficacy. 4SC-101 was also administered for 6 days after the intracolonic administration of TNBS (20 mg in 50% ethanol) to female Balb/c mice. The colons were analyzed for overall macroscopic damage, ulceration, total length, distal segment weight, MPO activity, and histological pathology as indicators for the effectiveness of 4SC-101.
In vitro, 4SC-101 is a potent inhibitor of human DHODH, inhibits lymphocyte proliferation, and uniquely blocks phytohemagglutinin-stimulated IL-17 production by lymphocytes. In vivo, oral administration of 4SC-101 effectively improved both chronic DSS and acute TNBS colitis in mice. In these colitis models the overall efficacy profile of 4SC-101 was similar to that of dexamethasone.
4SC-101 is a novel immunosuppressive drug with excellent potential for the treatment of intestinal inflammation. (Inflamm Bowel Dis 2010)
1Penn State College of Medicine, Hummelstown, Pennsylvania
2Lophius Biosciences, Regensburg, Germany
3Universitätsklinikum Regensburg, Regensburg, Germany
44SC AG, Planegg-Martinsried, Germany
*Reprints: Penn State College of Medicine, Department of Pharmacology, 1214 Research Boulevard, Hummelstown, PA 17042
Received for publication 21 January 2010; Accepted 30 January 2010.
Published online 22 March 2010 in Wiley Online Library (wileyonlinelibrary.com).
†Funded by Procter & Gamble (P&G) Pharmaceuticals, Cincinnati OH, as well as by 4SC-AG, Planegg-Martinsreid, Germany. These corporate sponsors were not involved in the data analyses or reporting of the data.