An improved reporter identifies ruxolitinib as a potent and cardioprotective CaMKII inhibitor. Sci Transl Med 2023 Jun 21;15(701):eabq7839
Date
06/21/2023Pubmed ID
37343080Pubmed Central ID
PMC11022683DOI
10.1126/scitranslmed.abq7839Scopus ID
2-s2.0-85163061900 (requires institutional sign-in at Scopus site) 55 CitationsAbstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits of CaMKII inhibition in numerous preclinical models of heart disease, translation of CaMKII antagonists into humans has been stymied by low potency, toxicity, and an enduring concern for adverse effects on cognition due to an established role of CaMKII in learning and memory. To address these challenges, we asked whether any clinically approved drugs, developed for other purposes, were potent CaMKII inhibitors. For this, we engineered an improved fluorescent reporter, CaMKAR (CaMKII activity reporter), which features superior sensitivity, kinetics, and tractability for high-throughput screening. Using this tool, we carried out a drug repurposing screen (4475 compounds in clinical use) in human cells expressing constitutively active CaMKII. This yielded five previously unrecognized CaMKII inhibitors with clinically relevant potency: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. We found that ruxolitinib, an orally bioavailable and U.S. Food and Drug Administration-approved medication, inhibited CaMKII in cultured cardiomyocytes and in mice. Ruxolitinib abolished arrhythmogenesis in mouse and patient-derived models of CaMKII-driven arrhythmias. A 10-min pretreatment in vivo was sufficient to prevent catecholaminergic polymorphic ventricular tachycardia, a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. At cardioprotective doses, ruxolitinib-treated mice did not show any adverse effects in established cognitive assays. Our results support further clinical investigation of ruxolitinib as a potential treatment for cardiac indications.
Author List
Reyes Gaido OE, Pavlaki N, Granger JM, Mesubi OO, Liu B, Lin BL, Long A, Walker D, Mayourian J, Schole KL, Terrillion CE, Nkashama LJ, Hulsurkar MM, Dorn LE, Ferrero KM, Huganir RL, Müller FU, Wehrens XHT, Liu JO, Luczak ED, Bezzerides VJ, Anderson MEAuthor
Brian L. Lin PhD Assistant Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsArrhythmias, Cardiac
Calcium
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Child
Heart Diseases
Humans
Mice
Myocytes, Cardiac
Nitriles
Pyrazoles
Pyrimidines
