George Kokotos
University of Athens, Greece
Title: Targeting the phospholipase A2 – Autotaxin Axis: A challenge to develop novel agents for the treatment of inflammatory and autoimmune diseases
Biography
Biography: George Kokotos
Abstract
Phospholipases A2 (PLA2) are enzymes that hydrolyze the sn-2 ester bond of the membrane phospholipids releasing free fatty acids and lysophospholipids. Arachidonic acid may be converted into a variety of eicosanoids by various enzymes, while lysophosphatidylcholine into lysophosphatidic acid (LPA) by a secreted enzyme that exhibits lysophospholipase D activity known as autotaxin (ATX). Both enzymes are involved in the production of inflammatory mediators and thus, constitute attractive targets for the development of novel agents for the treatment of inflammatory diseases. In addition, increased ATX expression and LPA production have been detected in a variety of cancers, which renders this enzyme a target for cancer treatment. A variety of small molecule PLA2 inhibitors have been developed and some of them reached clinical trials. In the case of ATX, several inhibitors have been reported, however only limited studies using animal models are known. In our labs, we have developed several classes of novel PLA2 inhibitors, including 2-oxoamides and thiazolyl ketones targeting GIVA cPLA2, and fluoroketones targeting GVIA iPLA2. We have recently shown that administration of fluoroketone FKGK18 to non-obese diabetic mice significantly reduced diabetes incidence in association with improved glucose homeostasis, and β-cell preservation. In this presentation, we will discuss our most recent potent PLA2 and ATX inhibitors. We will present two novel classes of highly potent inhibitors: 2-oxoesters for GIVA cPLA2 and beta-lactones for GVIA iPLA2. Such inhibitors were found to suppress the release of PGE2 in renal mesangial cells. A lipidomic approach to monitor the effect of inhibitors will be discussed.