ipla2

MAFP (Methyl Arachidonyl Fluorophosphonate) is an effective, active-site directed irreversible inhibitor of anandamide amidase, cPLA2, and iPLA2.

FKGK11 is a potent inhibitor of GVIA iPLA2.

FKGK 18 is an inhibitor of group VIA (GVIA) calcium-independent phospholipase A2 (iPLA2). It inhibits GVIA iPLA2 by 99.9% at 0.091 mole fraction in a mixed micelle activity assay and is selective for GVIA iPLA2 over GIVA cPLA2 and GV sPLA2 where it shows 80.8 and 36.8% inhibition, respectively. FKGK 18 inhibits iPLA2β activity in cytosolic extracts from INS-1 cells overexpressing iPLA2β (IC50 = ~50 nM) as well as iPLA2γ activity in mouse heart membrane fractions (IC50s = ~1-3 μM). It inhibits glucose-induced increases in prostaglandin E2 production and insulin secretion in human pancreatic islets when used at a concentration of 10 μM and inhibits thapsigargin-induced apoptosis in INS-1 cells overexpressing iPLA2β in a concentration-dependent manner. FKGK 18 (20 mg/kg, 3 times per week) reduces blood glucose levels in an intraperitoneal glucose tolerance test, decreases the incidence of diabetes, and increases serum insulin levels in non-obese diabetic (NOD) mice.

The phospholipases are an extensive family of lipid hydrolases that function in cell signaling, digestion, membrane remodeling, and as venom components. The calcium-independent phospholipases (iPLA2) are a PLA2 subfamily closely associated with the release of arachidonic acid in response to physiologic stimuli. (R)-Bromoenol lactone ((R)-BEL) is an irreversible, chiral, mechanism-based inhibitor of calcium-independent phospholipase γ (iPLA2γ). Unlike (S)-BEL, (R)-BEL does not inhibit iPLA2β except at high doses of 20-30 μM. (R)-BEL inhibits human recombinant iPLA2γ with an IC50 of approximately 0.6 μM.

GK187 is a selective and potent Group VIA calcium-independent phospholipase A2 (GVIA iPLA2) inhibitor, used in the study of neurological disorders.

Arachidonoyl Thio-PC is a substrate for various phospholipase A2s (PLA2s), including sPLA2, cPLA2, and iPLA2. Cleavage of the sn-2 fatty acid by PLA2 produces a free thiol that reacts with chromogenic reagents like DTNB (Ellman's reagent) and DTP, facilitating PLA2 activity quantitation. Isozyme-specific cPLA2 activity can be measured by excluding or inhibiting sPLA2 and iPLA2 activities in the assay.

GSK563 is a potent GVIA iPLA2 inhibitor (XI(50) 0.0000021, IC50 1 nM). GSK563 is 22 000 times more active against GVIA iPLA2 than GIVA cPLA2. It was found to reduce β-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes.

GK563, a selective Ca 2+-independent phospholipase A2 (GVIA iPLA2) inhibitor, exhibits a potent IC50 value of 1 nM and demonstrates 22,000-fold greater activity against GVIA iPLA2 compared to GIVA cPLA2. Its efficacy in reducing β-cell apoptosis triggered by proinflammatory cytokines suggests potential therapeutic benefits in combating autoimmune disorders, including type 1 diabetes.