title: Evaluation of the potential synergism of imatinib-related poly kinase inhibitors using growth factor stimulated proteoglycan synthesis as a model response.
abstract: BACKGROUND
  Tyrosine kinase inhibitors were the first class of smart drugs being specifically designed to inhibit a disease causing target. There is a very important but unresolved question as whether or not the overall therapeutic role of an individual tinib results from an action at its primary target, a single most likely, tyrosine kinase, or from the combined or aggregate action at the multiple targets which each tinib addresses.
  
  
  METHODS
  We selected a series of ten tinibs (gefitinib, sunitinib, lapatinib, erlotinib, imatinib, sorafenib, axitinib, vanitinib, bosutinib, dasatinib) with various known targets and investigated their activities in the inhibition of proteoglycan synthesis and GAG hyperelongation stimulated by a tyrosine kinase receptor agonist, platelet derived growth factor (PDGF) and for contrast, a serine/threonine kinase receptor agonist, TGF β and some downstream signalling pathways.
  
  
  RESULTS
  The inhibitory activity varied from little to total inhibition. The actions of the tinibs were directed more towards inhibition of the tyrosine kinase, PDGF receptor signalling pathway compared to the TGF β.
  
  
  CONCLUSIONS
  There was no suggestion of any synergistic effect arising from inhibition of multiple kinases as the most potent compound, dasatinib, is known to inhibit the broadest spectrum of kinases.
authors.affiliation: School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, QLD, Australia.|School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Bernard
authors.affiliation: School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.
authors.forename: Robel
authors.initials: R
authors.lastname: Getachew
authors.affiliation: School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Kamato
authors.affiliation: School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, QLD, Australia.
authors.forename: Lyna
authors.initials: L
authors.lastname: Thach
authors.affiliation: School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.|Department of Immunology, Monash University, Melbourne, VIC, Australia.
authors.forename: Narin
authors.initials: N
authors.lastname: Osman
authors.affiliation: School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.
authors.forename: Vincent
authors.initials: V
authors.lastname: Chan
authors.affiliation: Faculty of Health Sciences, University of Macau, Taipa, Macau.|China and Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zheng
authors.affiliation: School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, QLD, Australia.|School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.|Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou, China.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Little
mesh_terms: D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011509:Proteoglycans / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases
keywords: GAG hyperelongation; cell signalling; platelet derived growth factor; proteoglycan; tinibs; transforming growth factor-β