FDA-Approved Cancer Drug Ruxolitinib Shows Promise for Treating Cardiac Arrhythmias
核心洞察
Researchers from Johns Hopkins University and University of Chicago discovered that ruxolitinib, an FDA-approved cancer and skin condition drug, effectively inhibits CaMKII protein kinase linked to cardiac arrhythmias (搜索).
The team developed a novel biosensor called CaMKAR to screen nearly 5,000 FDA-approved drugs, identifying five previously unknown CaMKII inhibitors with ruxolitinib being the most effective.
In mouse models, a 10-minute application of ruxolitinib prevented catecholaminergic polymorphic ventricular tachycardia (搜索) and rescued atrial fibrillation (搜索) without causing adverse cognitive effects.
Researchers from Johns Hopkins University and the University of Chicago have identified ruxolitinib, an FDA-approved drug currently used to treat certain cancers (搜索) and skin conditions, as a potent inhibitor of CaMKII, a protein kinase critically linked to cardiac arrhythmias (搜索). The findings, published in Science Translational Medicine on June 21, 2023, represent a significant breakthrough in cardiac therapeutics through drug repurposing.
Novel Biosensor Enables Large-Scale Drug Screening
The research team, led by Mark Anderson, MD, PhD, Dean of the Biological Sciences Division at the University of Chicago, developed an innovative reporting technique to monitor CaMKII activity in living cells. Oscar Reyes Gaido, the study's first author and MD-PhD student, engineered a biosensor called CaMKAR (CaMKII Activity Reporter) using green fluorescent protein derived from jellyfish. This tool glows bright green whenever CaMKII becomes active, allowing real-time monitoring of enzyme activity in human heart cells.
"This biosensor will be very useful for studying how CaMKII activity changes in both healthy and pathological contexts," Reyes Gaido explained. "Existing methods can measure CaMKII activity, but they lack the versatility and resolution to track in real time and with high sensitivity."
Using this novel biosensor, researchers conducted a comprehensive drug repurposing screen testing 4,475 FDA-approved compounds on cultured human cardiomyocytes. The screen identified five previously unknown CaMKII inhibitors: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib.
Ruxolitinib Demonstrates Superior Efficacy
Among the five identified compounds, ruxolitinib proved most effective at inhibiting CaMKII activity in both cell and mouse models of CaMKII-driven arrhythmias. The drug, currently approved for treating blood and bone marrow cancers (搜索) as well as skin conditions including atopic dermatitis (搜索) and vitiligo (搜索), demonstrated remarkable therapeutic potential in cardiac applications.
In preclinical studies, a 10-minute application of ruxolitinib was sufficient to prevent catecholaminergic polymorphic ventricular tachycardia (搜索) (CPVT), a congenital condition that causes pediatric cardiac arrest, and rescue atrial fibrillation (搜索), the most common clinical arrhythmia. Importantly, mice treated with ruxolitinib showed no adverse cognitive effects when tested with memory and learning tasks.
Overcoming Historical Development Barriers
CaMKII, or Calcium and calmodulin-dependent protein kinase II (搜索), plays a crucial role in cardiomyocytes by maintaining calcium balance. While CaMKII activation facilitates rapid changes in heart activity such as fight-or-flight responses, overactivation can lead to impaired heart function, cell death, and arrhythmias.
The development of CaMKII inhibitors for cardiac treatment has been historically hindered by concerns about cognitive impacts, as the enzyme plays key roles in brain learning and memory processes. The discovery that ruxolitinib effectively inhibits CaMKII without reported cognitive problems addresses this longstanding obstacle.
"Finding an FDA approved drug means that millions of people have been taking CaMKII inhibitors, and in the case of ruxolitinib, there are no reported major problems with the brain," Anderson noted. "That should give pharma and biotech companies confidence that they could carry out development of a CaMKII inhibitor program, because the biggest obstacle seems to be surmountable."
Multiple Therapeutic Applications Envisioned
Anderson outlined several potential clinical applications for ruxolitinib-based cardiac treatments. The "pill in a pocket" approach would allow patients in early stages of atrial fibrillation (搜索) to take medication as symptoms arise. For CPVT patients who are often resistant to standard treatments, ruxolitinib-based therapy could provide an alternative option.
Additionally, evidence suggests that inhibiting CaMKII during heart attacks can prevent heart muscle death, potentially making such drugs part of standard emergency response protocols.
"There's been a long search for fundamental pathways that could be targets for therapeutics in arrhythmias," Anderson said. "This could be a finding that will translate relatively rapidly into people now since it's already been proven to be safe in humans."
The research was supported by multiple organizations including the American Heart Association, National Institutes of Health, and the Flight Attendant Medical Research Institute, with contributions from researchers at Boston Children's Hospital, Harvard Medical School, Baylor College of Medicine, and the University of Munster (搜索), Germany.