Specific inhibition of c-Raf activity by semapimod induces clinical remission in severe Crohn's disease.
There is a substantial need for novel treatment strategies in Crohn's disease (CD), a chronic relapsing inflammatory disease of the gut. In an earlier study, we reported clinical efficacy of a 2-wk treatment with semapimod (CNI-1493) in 12 patients with therapy resistant CD. The aim of this study was to identify the cellular target underlying semapimod action. In vitro experiments with murine macrophages showed impaired MAPK signaling and decreased cytokine production due to semapimod treatment. In vitro kinase assays revealed c-Raf as a direct molecular target of semapimod, and semapimod did not affect b-Raf enzymatic activity. Immunohistochemistry performed on paired colon biopsies obtained from CD patients (n = 6) demonstrated increased expression of phospho-MEK, the substrate of Raf. Strikingly, phospho-MEK levels were significantly decreased in patients with a good clinical response to semapimod, but no decrease in phospho-MEK expression was observed in a clinically nonresponsive patient. In conclusion, this study identifies c-Raf as a molecular target of semapimod action and suggests that decreased c-Raf activity correlates with clinical benefit in CD. Our observations indicate that c-Raf inhibitors are prime candidates for the treatment of CD.
Löwenberg
Mark
M
Laboratory of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. m.lowenberg@amc.uva.nl
Verhaar
Auke
A
van den Blink
Bernt
B
ten Kate
Fibo
F
van Deventer
Sander
S
Peppelenbosch
Maikel
M
Hommes
Daniel
D
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D003424:Crohn Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018664:Interleukin-12 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012720:Severity of Illness Index; D000813:Anilides; D006146:Guanidines
D016207:Cytokines; D006835:Hydrazones; D018664:Interleukin-12; D020928:Mitogen-Activated Protein Kinases; D047428:Protein Kinase Inhibitors; D019908:Proto-Oncogene Proteins c-raf; C097256:semapimod; D000813:Anilides; D006146:Guanidines