MK 886 is a 5-lipoxygenase-activating protein (FLAP) inhibitor and PPARα antagonist (IC50=30nM). MK 886 blocks leukotriene biosynthesis in intact leukocytes and human whole blood (IC50=3nM or 1.1μM). MK 886 can be used in research related to inflammatory diseases (such as asthma, arthritis) and cancers (such as gastric cancer, lung cancer)[1-4].
In vitro, under normoxic or hypoxic conditions, MK 886 (0.5μM) was used to treat human pulmonary artery endothelial cells for 24-72 hours. MK 886 significantly reduced endothelial cell proliferation[5]. MK 886 (25μM) was used to treat MM55.K mouse kidney tubular cells for 24 hours. MK 886 abrogated the metformin-induced upregulation of organic cation transporter-2 (OCT-2) and peroxisome proliferator-activated receptor α, and downregulated the expression of multidrug and toxin extrusion protein-1 (MATE-1)[6].
In vivo, MK 886 (3mg/kg; once daily) was intraperitoneally injected into mice for six consecutive days. MK 886 slightly increased climbing behavior and significantly reduced rest time in mice[7]. One hour before behavioral testing, MK 886 (10mg/kg) was intraperitoneally injected into Swiss mice. MK 886 significantly reduced the number of open arm entries in the elevated plus maze test in mice[8].
References:
[1] Kehrer JP, Biswal SS, La E, et al. Inhibition of peroxisome-proliferator-activated receptor (PPAR)alpha by MK886. Biochem J. 2001 Jun 15;356(Pt 3):899-906.
[2] Gillard J, Ford-Hutchinson AW, Chan C, et al. L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2 - dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol. 1989 May;67(5):456-64.
[3] Shi KN, Li PB, Su HX, et al. MK-886 protects against cardiac ischaemia/reperfusion injury by activating proteasome-Keap1-NRF2 signalling. Redox Biol. 2023 Jun;62:102706.
[4] Peres-Buzalaf C, de Paula L, Frantz FG, et al. Control of experimental pulmonary tuberculosis depends more on immunostimulatory leukotrienes than on the absence of immunosuppressive prostaglandins. Prostaglandins Leukot Essent Fatty Acids. 2011 Aug;85(2):75-81.
[5] Porter KM, Kang BY, Adesina SE, et al. Chronic hypoxia promotes pulmonary artery endothelial cell proliferation through H2O2-induced 5-lipoxygenase. PLoS One. 2014 Jun 6;9(6):e98532.
[6] Arruda AC, Perilhão MS, Santos WA, et al. PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice. Molecules. 2020 Jan 17;25(2):392.
[7] Uz T, Dimitrijevic N, Imbesi M, et al. Effects of MK-886, a 5-lipoxygenase activating protein (FLAP) inhibitor, and 5-lipoxygenase deficiency on the forced swimming behavior of mice. Neurosci Lett. 2008 May 9;436(2):269-72.
[8] Leo LM, Almeida-Corrêa S, Canetti CA, et al. Age-dependent relevance of endogenous 5-lipoxygenase derivatives in anxiety-like behavior in mice. PLoS One. 2014 Jan 8;9(1):e85009.