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

Aberrant signaling by transforming growth factor-β (TGF-β) 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-β 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.

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.

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.