Martyn D. Lewis, John P. McKew¹, Kathleen E. Neuzi, Takashi Akasaka*
Highly selective, potent inhibitors of the Src kinase paradigm are helping to unravel the functional importance of individual Src kinase isoforms, coupled with the development of new chemical probes designed for this purpose. Myocardial ischemia/reperfusion (I/R) remains an immediate therapeutic target. Inhibition of the Src kinase family, non-receptor protein tyrosine kinases normally regulated by ATP release, has been shown to lead to myocardial protection against I/R injury. The potential of Src kinase inhibition for the treatment of diseases remains to be validated. Numerous kinase inhibitors identified and examined within the last decade in a clinical research environment, predominantly in oncology, represent multi-targeted kinase inhibitors in which the primary and secondary targets are usually receptor tyrosine kinases. The considerable interest in the understanding of the functional role of the "Src family", particularly the contribution of the unique mammalian isoform, c-Yes, in influencing myocardial structure and function provides the concomitant potential to expand the drug discovery insights. Src kinase (Src) plays a key role in the regulation of normal cardiac function and in numerous diseases including myocardial infarction. Src arbitrates functional I/R-injury – in particular perturbing adrenergic signalling using inhibitors. But to achieve potent protection, Src-selective inhibitors have predominantly low micromolar IC50 estimates, targeting mostly receptor-tyrosine kinases. Highly selective "c-Yes" inhibitors have been developed for medicinal chemistry investigations as a starting point for the development of an orally bioavailable Src-selective inhibitor. In conclusion, recent developments in the medicinal chemistry of kinase inhibitors have sufficiently advanced to permit this study, in which a highly selective c-Yes inhibitor enables the first experimental elucidation of the effect of highly selective Src inhibition.
Keywords: Acute myocardial infarction; Src; Ischemia/reperfusion (I/R)
Copyright © 2020 by Takashi Akasaka et al.
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Research Article
DOI: http://dx.doi.org/10.18081/2333-5106/017-3/146-158
American Journal of BioMedicine Volume 8, Issue 2, pages 129-140
Received February 16, 2020; Accepted May 30, 2020; Published June 27, 2020