4SC-101, a novel small molecule dihydroorotate dehydrogenase inhibitor, suppresses systemic lupus erythematosus in MRL-(Fas)lpr mice.
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.
Kulkarni
Onkar P
OP
Medizinische Poliklinik-Innenstadt, University of Munich, Munich, Germany.
Sayyed
Sufyan G
SG
Kantner
Claudia
C
Ryu
Mi
M
Schnurr
Max
M
Sárdy
Miklós
M
Leban
Johann
J
Jankowsky
Ruediger
R
Ammendola
Aldo
A
Doblhofer
Robert
R
Anders
Hans-Joachim
HJ
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002264:Carboxylic Acids / Q000737:chemistry / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D000090722:Dihydroorotate Dehydrogenase; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000627:therapeutic use; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology; D008181:Lupus Nephritis / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D002264:Carboxylic Acids; D000090722:Dihydroorotate Dehydrogenase; D007166:Immunosuppressive Agents; D044925:Oxidoreductases Acting on CH-CH Group Donors