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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:
 [1]
  1. Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, Manitoba, R3E 0T5 (Canada)
Publication Date:
OSTI Identifier:
21344920
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 244; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2009.12.032; PII: S0041-008X(09)00539-0; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DAMAGE; ENZYME INHIBITORS; NEOPLASMS; PHOSPHOTRANSFERASES; RATS; RECEPTORS; SERINE; SPECIFICITY; THREONINE; TYROSINE; AMINO ACIDS; ANIMALS; CARBOXYLIC ACIDS; DISEASES; ENZYMES; HYDROXY ACIDS; MAMMALS; MEMBRANE PROTEINS; ORGANIC ACIDS; ORGANIC COMPOUNDS; PHOSPHORUS-GROUP TRANSFERASES; PROTEINS; RODENTS; TRANSFERASES; VERTEBRATES

Citation Formats

Hasinoff, Brian B., E-mail: B_Hasinoff@UManitoba.c. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity. United States: N. p., 2010. Web. doi:10.1016/j.taap.2009.12.032.
Hasinoff, Brian B., E-mail: B_Hasinoff@UManitoba.c. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity. United States. https://doi.org/10.1016/j.taap.2009.12.032
Hasinoff, Brian B., E-mail: B_Hasinoff@UManitoba.c. 2010. "The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity". United States. https://doi.org/10.1016/j.taap.2009.12.032.
@article{osti_21344920,
title = {The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity},
author = {Hasinoff, Brian B., E-mail: B_Hasinoff@UManitoba.c},
abstractNote = {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.},
doi = {10.1016/j.taap.2009.12.032},
url = {https://www.osti.gov/biblio/21344920}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 244,
place = {United States},
year = {Thu Apr 15 00:00:00 EDT 2010},
month = {Thu Apr 15 00:00:00 EDT 2010}
}