Induction of heart valve lesions by small-molecule ALK5 inhibitors.

Aberrant signaling by transforming growth factor-ß (TGF-ß) and its type I (ALK5) receptor has been implicated in a number of human diseases and this pathway is considered a potential target for therapeutic intervention. Transforming growth factor-ß signaling via ALK5 plays a critical role during heart development, but the role of ALK5 in the adult heart is poorly understood. In the current study, the preclinical toxicology of ALK5 inhibitors from two different chemistry scaffolds was explored. Ten-week-old female Han Wistar rats received test compounds by the oral route for three to seven days. Both compounds induced histopathologic heart valve lesions characterized by hemorrhage, inflammation, degeneration, and proliferation of valvular interstitial cells. The pathology was observed in all animals, at all doses tested, and occurred in all four heart valves. Immunohistochemical analysis of ALK5 in rat hearts revealed expression in the valves, but not in the myocardium. Compared to control animals, protein levels of ALK5 were unchanged in the heart valves of treated animals. We also observed a physeal dysplasia in the femoro-tibial joint of rats treated with ALK5 inhibitors, a finding consistent with a pharmacological effect described previously with ALK5 inhibitors. Overall, these findings suggest that TGF-ß signaling via ALK5 plays a critical role in maintaining heart valve integrity.

Cardiotoxicity associated with targeting kinase pathways in cancer.

Cardiotoxicity, also referred to as drug-induced cardiac injury, is an issue associated with the use of some small-molecule kinase inhibitors and antibody-based therapies targeting signaling pathways in cancer. Although these drugs have had a major impact on cancer patient survival, data have implicated kinase-targeting agents such as sunitinib, imatinib, trastuzumab, and sorafenib in adversely affecting cardiac function in a subset of treated individuals. In many cases, adverse cardiac events in the clinic were not anticipated based on preclinical safety evaluation of the molecule. In order to support the development of efficacious and safe kinase inhibitors for the treatment of cancer and other indications, new preclinical approaches and screens are required to predict clinical cardiotoxicity. Laboratory investigations into the underlying molecular mechanisms of heart toxicity induced by these molecules have identified potentially common themes including mitochondrial perturbation and modulation of adenosine monophosphate-activated protein kinase activity. Studies characterizing cardiac-specific kinase knockout mouse models have developed our understanding of the homeostatic role of some of these signaling mediators in the heart. Therefore, when considering kinases as potential future targets or when examining secondary pharmacological interactions of novel kinase inhibitors, these models may help to inform us of the potential adverse cardiac effects in the clinic.

Gender differences in drug toxicity.

Clinical data suggest that gender dimorphic profiles are emerging in terms of both drug efficacy and adverse drug reactions (ADRs). With an increasing emphasis on individualised therapies and the need to prevent drug attrition there is a compelling need to understand the molecular basis for gender dimorphic profiles in ADRs and the consequences. Classes of agents exhibiting gender-based variation in pharmaceutical efficacy and toxicity include anaesthetics, HIV-1 therapies and antiarrhythmic drugs. Body weight differences are often cited as a reason for differences in drug pharmacokinetics and subsequent toxicity. However, some studies accounted for these factors and still found significance suggesting that dosage versus body weight does not explain the outcome. Here, we present an overview of current understanding of gender-specific drug toxicity and present rational molecular explanations for these adverse events. There is mounting evidence in support of hormonal effects underpinning the majority of the ADR differences observed between the sexes.