CaMKII
CaMKII: A Highly Sought-After Target in Cardiovascular Medicine with Broad Potential
A Previously Undruggable Target
The Role of CaMKII
CaMKII is a protein kinase that plays a central role in normal cardiac function, but when CaMKII becomes hyperactivated, as occurs in a number of settings, it can cause several different cardiovascular diseases.
Normal contraction and relaxation of the heart requires increases and decreases of cytoplasmic calcium and depends on the normal function of CaMKII. CaMKII regulates and fine-tunes the cycling of calcium ions into and out of the cytoplasm of heart muscle cells (cardiomyocytes).
However, under certain conditions, CaMKII can become hyperactivated, resulting in disruption of normal calcium homeostasis, leading to arrythmias and heart failure. By inhibiting CaMKII in the setting of these diseases, and dampening the activity of this hyperactivated CaMKII, our goal is to correct the calcium cycling abnormalities that cause these cardiovascular diseases.
The figure below provides further detail on the process described above and the role of CaMKII.
Click the arrows to learn more about how CaMKII can become fixed in a hyperactivated state, and how inhibiting CaMKII can prevent its hyperactivation.
1. Calcium flows into the cell. With each heartbeat, the cardiomyocyte cell membrane depolarizes, which opens the L-type calcium channel, and leads to the flow of calcium ions into the cytoplasm of the cell.
2. CaMKII activation. CaMKII becomes activated by the binding of calcium/calmodulin and thereafter phosphorylates the L-type calcium channel, leading to more calcium flow into the cytoplasm.
3. Release of calcium ions. The calcium ions that enter the cell bind to and open ryanodine receptor 2 (RyR2), a membrane protein that forms a channel for calcium ion release from the sarcoplasmic reticulum, the main calcium-storage organelle within the cardiomyocyte, into the cytoplasm of the cardiomyocyte. The release of calcium ions from the sarcoplasmic reticulum is amplified by the phosphorylation of RyR2 by CaMKII.
4. Contraction. Entry of calcium ions into the cytoplasm of the cardiomyocyte allows them to activate the acto-myosin filaments, a collection of proteins that create heart muscle contraction, which ejects blood from the heart into the circulation.
5. Relaxation. Following contraction, the calcium ions are transported back into the sarcoplasmic reticulum or are extruded from the cell, which lowers calcium levels in the heart cells, leading to relaxation. In normal conditions, CaMKII returns to an inactive state.
6. Hyperactivation of CaMKII. In the setting of cardiovascular diseases, CaMKII can become hyperactivated, which means it phosphorylates its target proteins excessively. This causes the abnormal release of calcium ions from the sarcoplasmic reticulum into the cytoplasm at times when calcium release does not normally occur. This dysregulation of calcium ion cycling can lead to heart arrhythmias and heart failure.
Our Vision for CaMKII
Cardurion is the first company to test a CaMKII inhibitor in a clinical trial, a goal that has long eluded other pharmaceutical companies. We are currently conducting a Phase 1 clinical trial of our lead CaMKII inhibitor, and we are initiating a first Phase 2 clinical trial for the treatment of the rare genetic disease, catecholaminergic polymorphic ventricular tachycardia (CPVT). We plan to test our CaMKII inhibitors in this disease first, and then in more common cardiovascular diseases, such as heart failure and atrial fibrillation, in the future.
CPVT
∼1 in 10,000
Patient incidence in U.S.
Rare genetic disease that causes sudden arrhythmias, generally at times of high adrenaline levels, such as during exercise or strong emotion
Currently treated off-label or with surgical interventions/devices
Post-operative
Atrial Fibrillation
3-6 Million
People in the U.S. have AF
Post-operative complication in ∼40% of cardiovascular surgery cases
Treatments mostly include prophylaxis of repurposed drugs
Heart Failure
6.5 Million
People in the U.S. have HF
Pharmacologic or genetic inhibition of CaMKII has been shown to revers cardiac dysfunction in HF models
Caurdurion CaMKII inhibitors validated in preclinical HF models
