title: The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity.
abstract: The use of the new anticancer tyrosine kinase inhibitors (TKI) has revolutionized the treatment of certain cancers. However, the use of some of these results in cardiotoxicity. Large-scale profiling data recently made available for the binding of 7 of the 9 FDA-approved tyrosine kinase inhibitors to a panel of 317 kinases has allowed us to correlate kinase inhibitor binding selectivity scores with TKI-induced damage to neonatal rat cardiac myocytes. The tyrosine kinase selectivity scores, but not the serine-threonine kinase scores, were highly correlated with the myocyte damaging effects of the TKIs. Additionally, we showed that damage to myocytes gave a good rank order correlation with clinical cardiotoxicity. Finally, strength of TKI binding to colony-stimulating factor 1 receptor (CSF1R) was highly correlated with myocyte damage, thus possibly implicating this kinase in contributing to TKI-induced cardiotoxicity.
authors.affiliation: Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0T5. B_Hasinoff@UManitoba.ca
authors.forename: Brian B
authors.initials: BB
authors.lastname: Hasinoff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D054715:Cardiotoxins / Q000008:administration & dosage / Q000633:toxicity*; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D018390:Gene Targeting / Q000379:methods; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D054715:Cardiotoxins; D047428:Protein Kinase Inhibitors