FKGK 18

FKGK 18 is an inhibitor of group VIA (GVIA) calcium-independent phospholipase A₂ (iPLA₂).¹ 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).² It inhibits glucose-induced increases in prostaglandin E₂ (PGE₂; Item No. 14010) 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.³

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1. Kokotos, G., Hsu, Y.H., Burke, J.E., et al. Potent and selective fluoroketone inhibitors of group VIA calcium-independent phospholipase A₂. J. Med. Chem. 53(9), 3602-3610 (2010).

2. Ali, T., Kokotos, G., Magrioti, V., et al. Characterization of FKGK18 as inhibitor of group VIA Ca²⁺-independent phospholipase A₂ (iPLA₂β): Candidate drug for preventing β-cell apoptosis and diabetes. PLoS One 8(8), e71748 (2013).

3. Bone, R.N., Gai, Y., Magrioti, V., et al. Inhibition of Ca²⁺-independent phospholipase A₂β (iPLA₂β) ameliorates islet infiltration and incidence of diabetes in NOD mice. Diabetes 64(2), 541-554 (2015).