KAI-1455: A selective ε-protein kinase C activator



KAI-1455, a ε-protein kinase C activator in Phase I testing for the treatment of ischemia-induced reperfusion injury, is being developed. The ε-PKC (ε-protein kinase C) activator was first described in 1999, and its sequence is (HDAPIGYD; PKC 85-92). Both peptides are conjugated via a Cys S-S bond to a cell permeable peptide with 11-amino acid. And the arginine-rich sequence of the HIV type 1 transactivator protein (TAT47-57; termed "carrier peptide") enables the delivery of the peptides across biological membranes. The peptides are highly selective for ε-PKC and they do not affect the activity/function of other PKC isozymes, even the highly homologous ε-PKC. Some studies have shown that selective agonist of PKC may be useful for patients with ischemic heart disease.

Pharmacologic action

The ε-PKC selective agonist derived from ε-PKC (amino acids 85 to 92 [HDAPIGYD]) was conjugated to TAT47-57 peptide by an S-S conjugation through free cysteines at the C terminus of each peptide. The peptide activator mainly inhibits intra-molecular interaction within the enzyme and its receptor for activated C-kinase, thus selectively triggering ε-PKC activation. Some studies have shown that a selective ε-PKC activator peptide confers cardioprotective effects on ischemia-reperfusion injury in various cell culture and isolated perfused heart models. Importantly, ε-PKC activator acts as a cardiac preconditioning-mimicking agent, it is cardioprotective when delivered before the ischemic event. Previous studies showed that ε-PKC activator inhibits human cardiac Na+ channels, activates human delayed rectifying K+ channels expressed in Xenopus oocytes, and inhibits the L-type Ca2+ channel in rat ventricular myocytes.


Some trial results show that selective ε-PKC activation by ε-PKC activator induces endothelial cell activation through a novel mechanism and increases cell growth, migration and capillary like sprouting, indicating that activated ε-PKC elicits a typical angiogenic phenotype. Specifically, ε-PKC activator treatment reduced infarct size and improved cardiac function and troponin T release, resulting in fewer cases of ventricular fibrillation during ischemia-reperfusion. At the same time, ε-PKC activator treatment during ischemia induces cardioprotection and reduces ventricular tachyarrhythmias in a porcine model in vivo. Fortunately, echocardiography or pathological examination of mice and pig treated with ε-PKC activators for 10 days showed no change in their body or heart weight, blood pressure, heart rate or cardiac contractility. Thus, sustained systemic delivery of ε-PKC activator induced a dose-dependent cardioprotection.

Pharmacokinetics and metabolism

In mice and pig models, some studies have demonstrated that ε-PKC activator is taken up by various tissues such as the liver, kidney, cardiac myocytes and endothelial cells and heart after an intravenous injection and it can be quickly cleared from the systemic circulation.


1. Koichi Inagaki, Rebecca Begley, Fumiaki Ikeno, Daria Mochly-Rosen. Cardioprotection by ε-protein kinase C activation from ischemia continuous delivery and antiarrhythmic effect of an ε-protein kinase C-activating peptide. Circulation, 2005, 111(1), 44-50.

2. Martina Monti, Sandra Donnini, Lucia Morbidelli, Antonio Giachetti, Daria Mochly-Rosen, Paolo Mignatti, Marina Ziche. PKCε activation promotes FGF-2 exocytosis and induces endothelial cell proliferation and sprouting. Journal of Molecular and Cellular Cardiology, 2013, 63, 107-117.

3. Grant Budas, Helio Miranda Costa Junior, Julio Cesar Batista Ferreira, and Deborah Schechtman, Identification of εPKC targets during cardiac ischemic injury. Circ J. 2012, 76(6), 1476-1485.

4. Mark Restivo, Dmitry O. Kozhevnikov, Yongxia S. Qua. Activation of ε-PKC reduces reperfusion arrhythmias and improves recovery from ischemia: Optical mapping of activation patterns in the isolated guinea-pig heart. Biochemical and Biophysical Research Communications, 2012, 426, 237-241.

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