Intracellular tyrosine kinases as novel targets for anti-fibrotic therapy in systemic sclerosis.
Tissue fibrosis is a major cause of death in SSc, but therapies that target selectively fibrosis are not yet available for routine clinical use. Recent pre-clinical studies suggest that selective tyrosine kinase inhibitors that target c-Abl, PDGF receptor or Src kinases might be promising targets for anti-fibrotic approaches. Dual inhibition of c-Abl and PDGF receptor by imatinib and nilotinib, and inhibition of Src kinases either selectively by SU6656 or in combination with c-Abl and PDGF by dasatinib exerted potent anti-fibrotic effects. Imatinib, nilotinib, dasatinib and SU6656 reduced dose-dependently the synthesis of extracellular matrix protein in human dermal fibroblasts in vitro and prevented fibrosis in the mouse model of bleomycin-induced skin fibrosis. Clinical data from patients with chronic myelogenous leukaemia suggest that imatinib, nilotinib and dasatinib are well tolerated. Based on the promising pre-clinical data, imatinib is currently evaluated in clinical trials for the treatment of fibrosis in SSc and trials with other tyrosine kinase inhibitors are in preparation.
Distler
J H W
JH
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Germany. joerg.distler@uk-erlangen.de
Distler
O
O
D000818:Animals; D001549:Benzamides; D002986:Clinical Trials as Topic; D000069439:Dasatinib; D005355:Fibrosis; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000201:enzymology; D012867:Skin / Q000201:enzymology; D013449:Sulfonamides / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use
D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C416927:SU 6656; D013449:Sulfonamides; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib; D000069439:Dasatinib