MK-886

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MK-886
MK-886.svg
Names
Preferred IUPAC name
3-{3-(tert-Butylsulfanyl)-1-[(4-chlorophenyl)methyl]-5-(propan-2-yl)-1H-indol-2-yl}-2,2-dimethylpropanoic acid
Other names
L-663536
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
MeSH L+663536
PubChem CID
UNII
  • InChI=1S/C27H34ClNO2S/c1-17(2)19-10-13-22-21(14-19)24(32-26(3,4)5)23(15-27(6,7)25(30)31)29(22)16-18-8-11-20(28)12-9-18/h8-14,17H,15-16H2,1-7H3,(H,30,31)
    Key: QAOAOVKBIIKRNL-UHFFFAOYSA-N
  • CC(C)C1=CC2=C(C=C1)N(C(=C2SC(C)(C)C)CC(C)(C)C(=O)O)CC3=CC=C(C=C3)Cl
Properties
C27H34ClNO2S
Molar mass 472.083
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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MK-886, or L-663536, is a leukotriene antagonist. It may perform this by blocking the 5-lipoxygenase activating protein (FLAP), thus inhibiting 5-lipoxygenase (5-LOX), [1] and may help in treating atherosclerosis. [2]


MK-886 is a synthesized chemical compound known for its role in inhibiting the 5-lipoxygenase-activating protein (FLAP). Key part in leukotriene biosynthesis. It has potential therapeutic applications in different types of cancer when paired up with other synthetically made chemical compounds. This includes the cancer cells doing apoptosis and suppress tumor cell growth independent from leukotriene inhibition with some cases.

Mechanism of Action

Originally MK-886 was made as a FLAP inhibitor which has some interference with the leukotriene pathway. This is done by blocking 5-lipoxygenase which is an enzyme which aids in the synthesis of pro-inflammatory leukotrienes which is linked to some inflammatory diseases and cancers.

Cancer Research and Apoptosis

Several studies have shown the anti-cancer potential of MK-886. In a 2004 study MK-886 was shown to induce apoptosis in gastric cancer cells through the upregulation of the pro-apoptotic proteins p27^kip1 and Bax. This shows that the compound may promote cell death through a pathway that is at least partially independent of its role in leukotriene inhibition. [3]

In another study from 2007 researchers investigated the combined inhibition of 5-lipoxygenase and cyclooxygenase-2 (COX-2) in premalignant and malignant lung cell lines. MK-886 when combined with a COX-2 inhibitor significantly enhanced growth arrest and cell death. This shows a synergistic effect when targeting multiple inflammatory pathways in cancer therapy. [4]

Therapeutic Potential

Due to its ability to both function in inflammatory and apoptotic pathways MK-886 has gained some recognition as a therapeutic agent for not a solo case of inflammatory diseases but also for cancers where leukotriene signaling, specially, helps to promote the tumors survival and growth.

References

  1. ↑ Jun, Joon-Il; Lau, Lester F. (July 2010). "The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing". Nature Cell Biology. 12 (7): 676–685. doi:10.1038/ncb2070. ISSN   1465-7392. PMC   2919364 . PMID   20526329.
  2. ↑ Jawien, J.; Gajda, M.; Rudling, M.; Mateuszuk, L.; Olszanecki, R.; Guzik, T. J.; Cichocki, T.; Chlopicki, S.; Korbut, R. (March 2006). "Inhibition of five lipoxygenase activating protein (FLAP) by MK-886 decreases atherosclerosis in apoE/LDLR-double knockout mice". European Journal of Clinical Investigation. 36 (3): 141–146. doi:10.1111/j.1365-2362.2006.01606.x. PMID   16506957. S2CID   44897529.
  3. ↑ Fan, Xiao Ming; Tu, Shui Ping; Lam, Shiu Kum; Wang, Wei Ping; Wu, Jing; Wong, Wai Man; Yuen, Man Fung; Lin, Marie Chia Mi; Kung, Hsiange Fu; Wong, Benjamin Chun-Yu (January 2004). "Five-lipoxygenase-activating protein inhibitor MK-886 induces apoptosis in gastric cancer through upregulation of p27kip1 and bax". Journal of Gastroenterology and Hepatology. 19 (1): 31–37. doi:10.1111/j.1440-1746.2004.03194.x. ISSN   0815-9319. PMID   14675240.
  4. ↑ Schroeder, Claudia P.; Yang, Peiying; Newman, Robert A.; Lotan, Reuben (2007). "Simultaneous inhibition of COX-2 and 5-LOX activities augments growth arrest and death of premalignant and malignant human lung cell lines". Journal of Experimental Therapeutics & Oncology. 6 (3): 183–192. ISSN   1359-4117. PMID   17552358.
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