The oral Ca/calmodulin‐dependent kinase II inhibitor RA608 improves contractile function and prevents arrhythmias in heart failure

Abstract

Aims Excessive activation of Ca/calmodulin-dependent kinase II (CaMKII) is of critical importance in heart failure (HF) and atrial fibrillation. Unfortunately, lack of selectivity, specificity, and bioavailability have slowed down development of inhibitors for clinical use. We investigated a novel CaMKIIδ/CaMKII-selective, ATP-competitive, orally available CaMKII inhibitor (RA608) on right atrial biopsies of 119 patients undergoing heart surgery. Furthermore, we evaluated its oral efficacy to prevent deterioration of HF in mice after transverse aortic constriction (TAC). Methods and results In human atrial cardiomyocytes and trabeculae, respectively, RA608 significantly reduced sarcoplasmic reticulum Ca leak, reduced diastolic tension, and increased sarcoplasmic reticulum Ca content. Patch-clamp recordings confirmed the safety of RA608 in human cardiomyocytes. C57BL6/J mice were subjected to TAC, and left ventricular function was monitored by echocardiography. Two weeks after TAC, RA608 was administered by oral gavage for 7 days. Oral RA608 treatment prevented deterioration of ejection fraction. At 3 weeks after TAC, ejection fraction was 46.1 ± 3.7% (RA608) vs. 34.9 ± 2.6% (vehicle), n = 9 vs. n = 12, P < 0.05, ANOVA, which correlated with significantly less CaMKII autophosphorylation at threonine 287. Moreover, a single oral dose significantly reduced inducibility of atrial and ventricular arrhythmias in CaMKIIδ transgenic mice 4 h after administration. Atrial fibrillation was induced in 6/6 mice for vehicle vs. 1/7 for RA608, P < 0.05, 'n À 1' χ 2 test. Ventricular tachycardia was induced in 6/7 for vehicle vs. 2/7 for RA608, P < 0.05, 'n À 1' χ 2 test. Conclusions RA608 is the first orally administrable CaMKII inhibitor with potent efficacy in human myocytes. Moreover, oral administration potently inhibits arrhythmogenesis and attenuates HF development in mice in vivo.

CaMKII, that binds with ligustilide, as a potential drug target of Suxiao jiuxin pill, a traditional Chinese medicine to dilate thoracic aorta

“… 1 Although blocking voltage‐gated calcium channels with specific antagonists stands as an optimal therapeutic strategy, 2 targeting Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) may also be a suitable approach, as this enzyme also plays an important role in the regulation of Ca 2+ ‐related physiological functions 3 , 4 and cardiovascular diseases. 5 , 6 Herein, we reveal a novel mechanism of CaMKII covalent inhibition by one kind of the phthalides present in Suxiao Jiuxin pills (SX), a traditional Chinese medicine frequently used for the treatment of cardiovascular disease.…”

CaMKII: Therapeutic target in vascular diseases warranted for Clinical and Translational Discovery?

“…Recently, four ATP-competitive CaMKII inhibitors, GS-680, AS105, RA608 and RA306, have been identified with the first three to inhibit arrhythmogenesis and RA306 to reverse cardiac dysfunction in dilated cardiomyopathy. [7][8][9][10] Using a high-throughput screening system for the kinase activity of CaMKII-δ9, we recently identified Hesperadin as a specific ATP-competitive inhibitor of CaMKII-δ with dual functions of cardioprotective and anti-tumour effects. Hesperadin directly binds to CaMKII-δ to inhibit its autonomous activity and avoid the off-target effects in CaMKII-α in the brain or the potassium channels in the hearts.…”

“…Additionally, KN‐62 and KN‐93 have many off‐targets, for example, CaMKI, CaMKIV, the potassium channels and the L‐type calcium channels, thus limiting its application. Recently, four ATP‐competitive CaMKII inhibitors, GS‐680, AS105, RA608 and RA306, have been identified with the first three to inhibit arrhythmogenesis and RA306 to reverse cardiac dysfunction in dilated cardiomyopathy 7–10 . Using a high‐throughput screening system for the kinase activity of CaMKII‐δ9, we recently identified Hesperadin as a specific ATP‐competitive inhibitor of CaMKII‐δ with dual functions of cardioprotective and anti‐tumour effects.…”

Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

“…Therefore, CaMKII has been considered as a target for the treatment of arrhythmias and heart failure [ 213 , 214 ]. Beneficial effects of CaMKII inhibition have been observed in experiments using animal models and cardiac myocytes from heart failure patients [ 214 , 215 , 216 , 217 ]. However, a recent report on the first clinical trial (Phase II) with the CaMKII inhibitor (NP202) revealed no prevention of post-MI heart failure [ 218 ].…”