MK591

IC50: 1.6 nM in a FLAP binding assay for MK-0591, which is the acid form of MK591 [1]

Arachidonate 5-lipoxygenase-activating protein is necessary for the activation of 5-lipoxygenase and therefore for the production of leukotrienes. MK-591 (MK-0591 sodium) is a selective and specific 5-Lipoxygenase-activating protein (FLAP) inhibitor.

In vitro: A series of performed inhibitor studies identified a specific inhibitor of 5-LO (MK-591), which has the ability to block JNK, MAPK and 5-LO signaling-cascades and drastically reducing the activity of pro-inflammatory cytokine TNF-a. Further evaluation of MK-591 utilizing cell proliferation assays in PBMCs, human proximal tubule cells showed a decrease in cell proliferation [2].

In vivo: Amyloid β peptide (Aβ) deposition in the brains of mice receiving MK-591 was significantly reduced when compared with controls. MK-591 treatment did not cause any change in the steady-state levels ofβ-site amyloid precursor protein cleaving enzyme 1, amyloid-β precursor protein or disintegrin and metalloproteinase domain-containing protein 10. By contrast, MK-591 caused a significant reduction of the γ-secretase complex, at the protein and message level [3].

Clinical trial: In an open-label and pilot study, short-term therapy with MK-591 reduces proteinuria by restoring glomerular size selectivity and thus reduces transglomerular protein trafficking. These benefits may result from glomerular leukotriene biosynthesis inhibition, but other MK-591-specific actions cannot be excluded [4].

References:
[1] Brideau C, Chan C, Charleson S, Denis D, Evans JF, Ford-Hutchinson AW, Fortin R, Gillard JW, Guay J, Guévremont D, et al.  Pharmacology of MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5- (quinolin-2-yl-methoxy)-indol-2-yl]-2,2-dimethyl propanoic acid), a potent, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol. 1992;70(6):799-807.
[2] Mendis C, Campbell K, Das R, Yang D, Jett M.  Effect of 5-lipoxygenase inhibitor MK591 on early molecular and signaling events induced by staphylococcal enterotoxin B in human peripheral blood mononuclear cells. FEBS J. 2008;275(12):3088-98.
[3] Jin Chu and Domenico Praticò.  Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer’s disease mouse model. J Neuroinflammation. 2012; 9: 127.
[4] Guasch A, Zayas CF, Badr KF.   MK-591 acutely restores glomerular size selectivity and reduces proteinuria in human glomerulonephritis. Kidney Int. 1999;56(1):261-7.

Effect of 5-lipoxygenase inhibitor MK591 on early molecular and signaling events induced by staphylococcal enterotoxin B in human peripheral blood mononuclear cells.[Pubmed:18479466]

FEBS J. 2008 Jun;275(12):3088-98.

Staphylococcal enterotoxin B (SEB) has been the focus of a number of studies due to its ability to promote septic shock and a massive impact on the human immune system. Even though symptoms and pathology associated with SEB is well known, early molecular events that lead to lethality are still poorly understood. Our approach was to utilize SEB induced human peripheral blood mononuclear cells (PBMCs) as a prototype module to further investigate the complexity of signaling cascades that may ultimately lead to lethal shock. Our study revealed the activation of multiple divergent intracellular pathways within minutes of SEB induction including components that interconnect investigated pathways. A series of performed inhibitor studies identified a specific inhibitor of 5-LO (MK591), which has the ability to block JNK, MAPK, p38kinase and 5-LO signaling-cascades and drastically reducing the activity of pro-inflammatory cytokine TNF-alpha. Further evaluation of MK591 utilizing cell proliferation assays in PBMCs, human proximal tubule cells and in vivo studies (monkey) showed a decrease in cell proliferation. The inhibitory effect of MK591 was reconfirmed at a genetic level through the utilization of a set of SEB specific genes. Signaling activities, inhibitor studies, cellular analysis and gene expression analysis in unison illustrated the significance of pathway interconnectors such as 5-LO as well as inhibiting such inter-connectors (using MK591) in SEB induced human PBMCs.

5-Lipoxygenase activating protein (FLAP) dependent leukotriene biosynthesis inhibition (MK591) attenuates Lipid A endotoxin-induced inflammation.[Pubmed:25025775]

PLoS One. 2014 Jul 15;9(7):e102622.

The Lipid A moiety of endotoxin potently activates TLR-4 dependent host innate immune responses. We demonstrate that Lipid-A mediated leukotriene biosynthesis regulates pathogen-associated molecular patterns (PAMP)-dependent macrophage activation. Stimulation of murine macrophages (RAW264.7) with E. coli 0111:B4 endotoxin (LPS) or Kdo2-lipid A (Lipid A) induced inflammation and Lipid A was sufficient to induce TLR-4 mediated macrophage inflammation and rapid ERK activation. The contribution of leukotriene biosynthesis was evaluated with a 5-lipoxygenase activating protein (FLAP) inhibitor, MK591. MK591 pre-treatment not only enhanced but also sustained ERK activation for up to 4 hours after LPS and Lipid A stimulation while inhibiting cell proliferation and enhancing cellular apoptosis. Leukotriene biosynthesis inhibition attenuated inflammation induced by either whole LPS or the Lipid A fraction. These responses were regulated by inhibition of the key biosynthesis enzymes for the proinflammatory eicosanoids, 5-lipoxygenase (5-LO), and cyclooxygenase-2 (COX-2) quantified by immunoblotting. Inhibition of leukotriene biosynthesis differentially regulated TLR-2 and TLR-4 cell surface expression assessed by flow cytometry, suggesting a close mechanistic association between TLR expression and 5-LO associated eicosanoid activity in activated macrophages. Furthermore, MK591 pre-treatment enhanced ERK activation and inhibited cell proliferation after LPS or Lipid A stimulation. These effects were regulated in part by increased apoptosis and modulation of cell surface TLR expression. Together, these data clarify the mechanistic association between 5-lipoxygenase activating protein-mediated leukotriene biosynthesis and 5-LO dependent eicosanoid metabolites in mediating the TLR-dependent inflammatory response after endotoxin exposure typical of bacterial sepsis.

MK591, a leukotriene biosynthesis inhibitor, induces apoptosis in prostate cancer cells: synergistic action with LY294002, an inhibitor of phosphatidylinositol 3'-kinase.[Pubmed:19906484]

Cancer Lett. 2010 May 28;291(2):167-76.

MK591 is a synthetic compound which specifically inhibits the activity of 5-Lox and is currently under development for the treatment of asthma. We observed that human prostate cancer cells treated with MK591 undergo apoptosis within hours of treatment. Apoptosis involves severe morphological alteration, externalization of phosphatidyl-serine, cleavage of PARP, and degradation of chromatin-DNA. MK591 also induced rapid activation of the stress kinase, c-Jun N-terminal kinase (JNK), which plays an important role in the apoptosis process. The phosphatidylinositol 3'-kinase-Akt/protein kinase B (PI3K/Akt) axis is a well-known pro-survival pathway which prevents apoptosis through defined anti-apoptotic mechanisms in a variety of cancer cells. Interestingly, we observed that MK591 triggers apoptosis in prostate cancer cells without inhibition of PI3K-Akt, or ERK. Moreover, it was observed that MK591 and LY294002 (an inhibitor of PI3K) exert synergistic effect in inducing apoptosis in prostate cancer cells. Altogether, these findings indicate that 5-Lox inhibition-induced apoptosis in prostate cancer cells occurs without inhibition of PI3K-Akt, or ERK, and suggest for the existence of an Akt- and ERK-independent survival mechanism(s) in these cancer cells maintained via signals generated by metabolites of 5-Lox.

MK591, a second generation leukotriene biosynthesis inhibitor, prevents invasion and induces apoptosis in the bone-invading C4-2B human prostate cancer cells: implications for the treatment of castration-resistant, bone-metastatic prostate cancer.[Pubmed:25875826]

PLoS One. 2015 Apr 15;10(4):e0122805.

Castration-resistant prostate cancer (CRPC) is a major clinical challenge for which no cure is currently available primarily because of the lack of proper understanding about appropriate molecular target(s). Previously we observed that inhibition of 5-lipoxygenase (5-Lox) activity induces apoptosis in some types of prostate cancer cells, suggesting an important role of 5-Lox in the viability of prostate cancer cells. However, nothing is known about the role of 5-Lox in the survival of castration-resistant, metastatic prostate cancer cells. Thus, we tested the effects of MK591, a second-generation, specific inhibitor of 5-Lox activity, on the viability and metastatic characteristics of CRPC cells. We observed that MK591 effectively kills the bone-invading C4-2B human prostate cancer cells (which bear characteristics of CRPC), but does not affect normal, non-cancer fibroblasts (which do not express 5-Lox) in the same experimental conditions. We also observed that MK591 dramatically inhibits the in vitro invasion and soft-agar colony formation of C4-2B cells. Interestingly, we found that treatment with MK591 dramatically down-regulates the expression of c-Myc and its targets at sub-lethal doses. In light of frequent over-activation of c-Myc in a spectrum of aggressive cancers (including CRPC), and the challenges associated with inhibition of c-Myc (because of its non-enzymatic nature), our novel findings of selective killing, and blockade of invasive and soft-agar colony-forming abilities of the castration-resistant, bone-metastatic C4-2B prostate cancer cells by MK591, open up a new avenue to attack CRPC cells for better management of advanced prostate cancer while sparing normal, non-cancer body cells.

Quiflapon sodium (MK-591 sodium) is a selective and specific 5-Lipoxygenase-activating protein (FLAP) inhibitor. Quiflapon sodium is an orally active Leukotriene biosynthesis inhibitor. Induces apoptosis.

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