Abstract

Cancer is one of the most common causes of death worldwide. In response to this, there has been a vast development in pharmacological anti-cancer therapies. Unfortunately, many of these therapies induce cardiac dysfunction and ultimately life shortening conditions such as heart failure, myocardial infarction and arrhythmias. As a result, their dose and thus anti-cancer efficacy is limited. This highlights the need for development of more cardio-safe anti-cancer drugs. One potential class of anti-cancer drug, which has shown promise both as an adjuvant and mono-therapy, is the checkpoint kinase (ChK) inhibitors. The development of existing ChK inhibitors has largely been abandoned due to associated cardiotoxicity demonstrated during clinical trials. This study takes a backwards step towards in vitro research into ChK inhibitors, with the aim of improving understanding of the molecular mechanisms of the cardiotoxicity exhibited by the drug. As identification of mechanisms has been elusive to the research field thus far, success in this study could lead to redesigns of existing cardiotoxic ChK inhibitors or development of new cardio-safe ChK inhibitors. Moreover, a more complete understanding will aid detection of early cardiotoxicity in vivo and thus could be potentially beneficial as a cardiotoxicity screening tool. This study has looked particularly at how the Ca2+ homeostasis is perturbed by the proven in vivo cardiotoxic ChK inhibitor, AZD7762 as well as 5 novel ChK inhibitors provided by a pharmaceutical company.