HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

4SC-101, a novel small molecule dihydroorotate dehydrogenase inhibitor, suppresses systemic lupus erythematosus in MRL-(Fas)lpr mice.

Abstract
Immunosuppressive treatments of systemic lupus (SLE) remain associated with significant toxicities; hence, compounds with better toxicity profiles are needed. Dihydroorotate dehydrogenase (DHODH) inhibition with leflunomide has proven to be effective in autoimmune diseases including SLE, but leflunomide can cause a variety of side effects. We hypothesized that 4SC-101, a novel DHODH inhibitor with a more favorable toxicity profile, would be as effective as high-dose cyclophosphamide (CYC) in controlling experimental SLE of female MRL(Fas)lpr mice. Daily oral gavage of 30, 100, and 300 mg/kg 4SC-101 from 12 to 22 weeks of age was compared with either vehicle or CYC treatment (30 mg/kg/week, i.p.) in terms of efficacy and toxicity. Three hundred milligrams per kilogram 4SC-101 was as effective as CYC in depleting spleen autoreactive T cells, B cells, and plasma cells as well as the respective DNA and RNA serum autoantibodies. This was associated with a comparable amelioration of the renal, dermal, and pulmonary SLE manifestations of MRL(Fas)lpr mice. However, even the highest dose of 4SC-101 had no effect on bone marrow neutrophil counts, which were significantly reduced in CYC-treated mice. Together, the novel DHODH inhibitor 4SC-101 is as effective as high dose CYC in controlling SLE without causing myelosuppression. Hence, DHODH inhibition with 4SC-101 might be suitable to treat active SLE with fewer side effects than CYC.
AuthorsOnkar P Kulkarni, Sufyan G Sayyed, Claudia Kantner, Mi Ryu, Max Schnurr, Miklós Sárdy, Johann Leban, Ruediger Jankowsky, Aldo Ammendola, Robert Doblhofer, Hans-Joachim Anders
JournalThe American journal of pathology (Am J Pathol) Vol. 176 Issue 6 Pg. 2840-7 (Jun 2010) ISSN: 1525-2191 [Electronic] United States
PMID20413687 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carboxylic Acids
  • Dihydroorotate Dehydrogenase
  • Immunosuppressive Agents
  • Oxidoreductases Acting on CH-CH Group Donors
Topics
  • Animals
  • B-Lymphocytes (drug effects, immunology)
  • Carboxylic Acids (chemistry, therapeutic use)
  • Clinical Trials as Topic
  • Dihydroorotate Dehydrogenase
  • Disease Models, Animal
  • Female
  • Humans
  • Immunosuppressive Agents (chemistry, therapeutic use)
  • Kidney (cytology, drug effects, metabolism, pathology)
  • Lupus Erythematosus, Systemic (drug therapy, enzymology, immunology)
  • Lupus Nephritis (drug therapy, pathology)
  • Mice
  • Mice, Inbred MRL lpr
  • Molecular Structure
  • Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors)
  • T-Lymphocytes (drug effects, immunology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: