Evaluation of the potential synergism of imatinib-related poly kinase inhibitors using growth factor stimulated proteoglycan synthesis as a model response
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Getachew, Robel
Kamato, Danielle
Thach, Lyna
Osman, Narin
Chan, Vincent
Zheng, Wenhua
Little, Peter J
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Abstract
Introduction 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. Conclusion 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.
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Journal of Pharmacy and Pharmacology
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68
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3
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© 2016 Royal Pharmaceutical Society. This is the peer reviewed version of the following article: Evaluation of the potential synergism of imatinib-related poly kinase inhibitors using growth factor stimulated proteoglycan synthesis as a model response, Journal of Pharmacy and Pharmacology, 68 (3), 368-378, 2016, which has been published in final form at https://doi.org/10.1111/jphp.12530. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
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Pharmacology and pharmaceutical sciences
Medical physiology
Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
cell signalling
GAG hyperelongation
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Bernard, R; Getachew, R; Kamato, D; Thach, L; Osman, N; Chan, V; Zheng, W; Little, PJ, Evaluation of the potential synergism of imatinib-related poly kinase inhibitors using growth factor stimulated proteoglycan synthesis as a model response, Journal of Pharmacy and Pharmacology, 2016, 68 (3), pp. 368-378