Delcasertib: A Novel δ-Protein Kinase C Inhibitor

2018-08-18

Introduction 

Delcasertib, also known as KAI-9803, is a 23-amino acid peptide and δ-protein kinase C (δ-PKC) inhibitor. KAI-9803 derived from the δ-V1-1 portion of δ-PKC (termed "cargo peptide") and conjugated reversibly to the cell-penetrating peptide with 11-amino acid, arginine-rich sequence of the HIV type 1 transactivator protein (TAT47-57; termed "carrier peptide") via a disulfide bond. At the same time, KAI-9803 can relieve injury associated with ischemia and reperfusion in animal models of acute myocardial infarction (MI). Thus, KAI-9803 appears to be a promising treatment to target the myocardial damage and microvascular dysfunction.

Pharmacologic Action

KAI-9803 is a novel peptide that inhibits δ-PKC activity by selectively disrupting binding of activated δ-PKC with its receptor for activated C-kinase and does not affect activation or localization of other PKC isozymes, thereby preventing localization of δ-PKC to the mitochondria during periods of myocardial ischemia and reperfusion. It reaches steady state within 5-30 min after the start of intravenous infusion with a terminal half-life of 2-5 min. What's more, KAI-9803 improves pathological conditions in acute myocardial infarction and reduces pain via specific modulation of membrane-translocation of PKC delta or epsilon. Thus, KAI-9803 shows the sign of potential drug activity in this early-phase trial.

Function

Although KAI-9803 can inhibit δ-PKC activity by selectively disrupting binding of activated δ-PKC with its receptor for activated C-kinase, it does not affect activation or localization of other PKC isozymes. KAI-9803 administration at the end of ischemia has been found to reduce cardiac damage caused by ischemia-reperfusion in a rat model of acute myocardial infarction. Furthermore, in preclinical studies when given as a single intracoronary dose just before reperfusion, KAI-9803 reduced infarct size myocyte and endothelial cellular damage, enhanced early recovery of regional left ventricular contractility, and improved microvascular patency and function in animal models of acute myocardial infarction (MI). Meanwhile, KAI-9803 has an acceptable safety and tolerability profile when delivered via intracoronary injection during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.

Pharmacokinetics and Metabolism

Some studies have been conducted to demonstrate that KAI-9803 was taken up into various tissues such as the liver, kidney, cardiac myocytes and endothelial cells and heart (1.21μgeq/g tissue) after an intravenous injection. Fortunately, it can be quickly cleared from the systemic circulation. Furthermore, in vivo studies also suggested that rapid metabolism of KAI-9803 was occurred by 5 min coincident with that of tyrosine. Subsequently, the parent compound was rapidly eliminated from the circulation with a half-life of 1.58 min.

References:

1. Y Miyaji, S Walter, L Chen, A Kurihara, T Ishizuka. Distribution of KAI-9803, a novel δ-protein kinase C inhibitor, after intravenous administration to rats. Drug Metab Dispos., 2011, 39 (10), 1946-1953.

2. Bates E, et al. Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation, 2008, 117 (7), 886-896.

3. A. Michael Lincoff, MatthewRoe. Inhibition of delta-protein kinase C by delcasertib as an adjunct to primary percutaneous coronary intervention for acute anterior ST-segment elevation myocardial infarction: results of the PROTECTIONAMIR andomized controlled trial. European Heart Journal, 2014, 35 (37), 2516-2523.

Contact Us

Address:

Tel: |

Email:

Copyright © 2023 Creative Peptides. All rights reserved.