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

Am J Pathol. 2010 Jun;176(6):2840-7. doi: 10.2353/ajpath.2010.091227. Epub 2010 Apr 22.

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.

Trial registration: ClinicalTrials.gov NCT00820365 NCT01010581.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • Carboxylic Acids* / chemistry
  • Carboxylic Acids* / therapeutic use
  • Clinical Trials as Topic
  • Disease Models, Animal
  • Female
  • Humans
  • Immunosuppressive Agents* / chemistry
  • Immunosuppressive Agents* / therapeutic use
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Lupus Erythematosus, Systemic / drug therapy*
  • Lupus Erythematosus, Systemic / enzymology*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Nephritis / drug therapy
  • Lupus Nephritis / pathology
  • Mice
  • Mice, Inbred MRL lpr*
  • Molecular Structure
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology

Substances

  • Carboxylic Acids
  • Immunosuppressive Agents
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase

Associated data

  • ClinicalTrials.gov/NCT00820365
  • ClinicalTrials.gov/NCT01010581