An Improved Reporter Identifies Ruxolitinib as a Potent and Cardioprotective CaMKII Inhibitor

Authors

Oscar E Reyes Gaido
Nikoleta Pavlaki
Jonathan M Granger
Olurotimi O Mesubi
Bian Liu
Brian L Lin
Alan Long
David Walker
Joshua Mayourian
Kate L Schole
Chantelle E Terrillion
Lubika J Nkashama
Mohit M Hulsurkar
Lauren E Dorn
Kimberly M Ferrero
Richard L Huganir
Frank U Müller
Xander H T Wehrens
Jun O Liu
Elizabeth D Luczak
Vassilios J Bezzerides
Mark E Anderson

Publication Date

6-21-2023

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.abq7839

PMID

37343080

PMCID

PMC11022683

PubMedCentral® Posted Date

4-17-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Child, Humans, Mice, Arrhythmias, Cardiac, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Heart Diseases, Myocytes, Cardiac, Pyrazoles

Abstract

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.

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