Cardiovascular Toxicity Induced by Kinase Inhibitors: Mechanisms and Preclinical Approaches.
Chem Res Toxicol
; 33(1): 125-136, 2020 01 21.
Article
en En
| MEDLINE
| ID: mdl-31840498
ABSTRACT
Kinase inhibitors have transformed the treatment of many cancers and are showing the same promise for other indications including inflammatory diseases. This class of drugs is one of the most predominant in the pharmaceutical industry, but development and clinical utility is often limited by a broad spectrum of cardiovascular (CV) toxicities including QT prolongation and arrhythmia, left ventricular dysfunction, congestive heart failure, ischemia and myocardial infarction, and hypertension. In this review article, we provide a broad overview of the spectrum of CV events detected in clinical trials of kinase inhibitors and the known and proposed on- and off-target links between kinase inhibitor targets and these specific cardiotoxicities. We also examine the unique features of kinase inhibitors that have impeded complete mechanistic understanding of kinase inhibitor-associated cardiotoxicities and contributed to the disconnect between preclinical predictions and clinical findings. We then discuss various in vitro models currently in use that are amenable for high-throughput screening as well as lower throughput models that are valuable for mechanistic insight. These physiologically relevant models, together with newer "omic"-wide approaches will help to increase our understanding of the mechanisms underlying kinase inhibitor-associated cardiotoxicity and enable rational design of kinase inhibitors in the future.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Inhibidores de Proteínas Quinasas
/
Cardiotoxicidad
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Chem Res Toxicol
Asunto de la revista:
TOXICOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos