Systemic administration of the PRMT5 inhibitor GSK3326595 does not induce overt cardiotoxicity in the murine heart

Protein Arginine Methyltransferase (PRMT5) has emerged as a promising target for antineoplastic strategies. Given its oncogenic properties in promoting tumorigenesis and metastasis of several cancer entities, pharmacological approaches to inhibit the enzymatic activity of PRMT5 (PRMT5i) have gained particular attention. Among others, GSK3326595 is currently evaluated in clinical studies for the treatment of hematological malignancies. However, besides the pathophysiological relevance, PRMT5 is a ubiquitously expressed enzyme with essential cellular functions. Previous studies uncovered a substantial role in cardiomyocytes along with heart failure caused by loss of PRMT5 raising the question if PRMT5i may exert adverse effects on the cardiovascular system. Thus, we conducted comprehensive pharmacokinetic profiling of GSK3326595 in mice. We found that systemic administration leads to a homogenous distribution across organs and tissues. While major depression of hematopoiesis could be detected, we did not find detrimental impact on systolic function, cardiac morphology and homeostasis indicating differential pharmacodynamics on proliferating and postmitotic cells. In conclusion, systemic treatment with GSK3326595 shows no overt effects on the murine heart under the conditions tested in this study.