KAI-1678: A novel PKC-epsilon inhibitor

Introduction 

KAI-1678, a synthetic 21-amino acid, is a novel PKC-epsilon (ε-PKC) inhibitor with a molecular weight of 2541 Daltons. Meanwhile, it is a cell-permeable peptide composed of an active inhibitor of ε-PKC conjugated to a carrier peptide to aid delivery to the targeted intracellular site of action. The active moiety, an inhibitor of ε-PKC, is an 8-amino acid peptide, termed ε-V1-2 (EAVSLKPT). The carrier moiety is an arginine-rich 11-amino acid peptide derived from the transactivator (TAT) protein. It was developed to competitively and selectively inhibit the interaction of ε-PKC and its ε-RACK. Meanwhile, it can reduce hyperalgesia in a variety of inflammatory and neuropathic pain models. These studies suggest that KAI-1678 may represent a new therapeutic approach for the treatment of pain.

Pharmacologic action

KAI-1678 is a novel peptide that competes with activated ε-PKC for binding to its isozyme-specific docking protein, thus preventing ε-PKC translocation. Furthermore, KAI-1678 contains the peptide sequence -EAVSLKPT- that has been shown to block ε-PKC translocation and reduce hyperalgesia in a variety of inflammatory and neuropathic pain models. Preclinical pharmacology studies evaluated the efficacy of KAI-1678 in a carrageenan acute inflammatory pain model, as well as chronic constriction injury and L5 spinal nerve transaction rodent models of peripheral neuropathy. At the same time, the safety profile of KAI-1678 reveals that the compound is safe and well tolerated.

Function

KAI-1678 has been shown to be highly effective in reversing pain for both neuropathic and inflammatory pain, both of which have well validated epsilon PKC. Phase II clinical trial validated a selective, intracellular peptide-based ε-PKC inhibitor is effective in reversing allodynia, which is a primary component of neuropathic pain. Laboratory abnormalities of two patients were reported at prespecified clinically significant levels during the KAI-1678 infusion periods; levels of hemoglobin, hematocrit, and calcium is decreased in one patient, and calcium levels is decreased in another patient. Overall, administration of KAI-1678 and lidocaine is generally safe and well tolerated, with the most common adverse effects being headache and pain at the infusion site.

Pharmacokinetics and metabolism

The ε-PKC amino acid sequence that is mimicked in KAI-1678 is identical in rat and human, suggesting that similar pharmacology should occur in both species. Some studies have been conducted to demonstrate that KAI-1678 is taken up by various tissues after an intravenous injection. Fortunately, it can be quickly cleared from the systemic circulation.

References:

1. Michael J. Cousins, MBBS, Karen Pickthorn, The safety and efficacy of KAI-1678-An inhibitor of epsilon protein kinase C (ε-PKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: A crossover study design. Pain Medicine, 2013, 14, 533-540.

2. John E. Moodie, MB ChB, FRCA, FANZCA, A single-center, randomized, double-blind, active, and placebo-controlled study of KAI-1678, a novel PKC-epsilon inhibitor, in the treatment of acute postoperative orthopedic pain. Pain Medicine, 2013, 14, 916-924.

3. Velazquez KT, Mohammad H, Sweitzer SM. Protein kinase C in pain: Involvement of multiple isoforms. Pharmacol Res, 2007, 55, 578-589.