cx-4945 and ponatinib

Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP-binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca. The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single-cell Ca. Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti-SOICR agent VK-II-86.. Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti-SOICR activity may represent an improved treatment option for patients.

Topics: Animals; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Imidazoles; Ligands; Male; Muscle Cells; Naphthyridines; Phenazines; Protein Kinase Inhibitors; Pyridazines; Pyrimidines; Rats; Rats, Sprague-Dawley; Ryanodine Receptor Calcium Release Channel; Single-Cell Analysis; Structure-Activity Relationship; Sunitinib