OTSSP167

MELK inhibitor CAS# 1431697-89-0

OTSSP167

Catalog No. BCC4314----Order now to get a substantial discount!

Product Name & Size Price Stock
OTSSP167:5mg $149.00 In stock
OTSSP167:10mg $253.00 In stock
OTSSP167:25mg $596.00 In stock
OTSSP167:50mg $1043.00 In stock
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  • OTSSP167

    Catalog No.:BCC4314
    CAS No.:1431697-89-0

Quality Control of OTSSP167

Quality Control & MSDS

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Chemical structure

OTSSP167

3D structure

Chemical Properties of OTSSP167

Cas No. 1431697-89-0 SDF Download SDF
PubChem ID 71543332 Appearance Powder
Formula C25H28Cl2N4O2 M.Wt 487.42
Type of Compound N/A Storage Desiccate at -20°C
Synonyms MELK inhibitor
Solubility Soluble to 0.5 mg/mL warmed (1.02 mM) in DMSO
Chemical Name 4-[7-acetyl-8-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1H-1,5-naphthyridin-2-ylidene]-2,6-dichlorocyclohexa-2,5-dien-1-one
SMILES CC(=O)C1=CN=C2C=CC(=C3C=C(C(=O)C(=C3)Cl)Cl)NC2=C1NC4CCC(CC4)CN(C)C
Standard InChIKey WZJUACDPTWDYSI-UHFFFAOYSA-N
Standard InChI InChI=1S/C25H28Cl2N4O2/c1-14(32)18-12-28-22-9-8-21(16-10-19(26)25(33)20(27)11-16)30-24(22)23(18)29-17-6-4-15(5-7-17)13-31(2)3/h8-12,15,17,30H,4-7,13H2,1-3H3,(H,28,29)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of OTSSP167

DescriptionOTSSP167 is an inhibitor of maternal embryonic leucine zipper kinase (MELK) with IC50 value of 0.41nM .
TargetsMELK    
IC500.41nM     

Protocol

Kinase Assay [1]
For in vitro kinase assay, MELK recombinant protein (0.4 μg) is mixed with 5 μg of each substrate in 20 μL of kinase buffer containing 30 mM Tris-HCl (pH), 10 mM DTT, 40 mM NaF, 10 mM MgCl2, 0.1 mM EGTA with 50 μM cold-ATP and 10 Ci of [γ-32P]ATP for 30 min at 30°C. The reaction Is terminated by addition of SDS sample buffer and boiled for 5 min prior to SDS-PAGE. The gel is dried and autoradiographed with intensifying screens at room temperature. OTSSP167 (final concentration of 10 nM) is dissolved in DMSO and added to kinase buffer before the incubation.

Cell Assay [1]
In vitro cell viability is measured by the colorimetric assay using Cell Counting Kit-8. Cells are plated in 100 μL in 96-well plates at a density that generates continual linear growth (A549, 1×103 cells; T47D, 3×103 cells; DU4475, 4×103 cells; 22Rv1, 6×103 cells; and HT1197, 2×103 cells, in 100 μL per well). The cells are allowed to adhere overnight before exposure to OTSSP167 for 72 hours at 37°C. Plates are read using a spectrophotometer at a wavelength of 450 nm. All assays are carried out in triplicate.

Animal Administration [1]
MDA-MB-231 cells are injected into the mammary fat pads of NOD.CB17-Prkdcscid/J mice. A549, MIAPaCa-2 and PC-14 cells (1×105 cells) are injected subcutaneously in the left flank of female BALB/cSLC-nu/nu mice. DU145 cells are injected subcutaneously in the left flank of male BALB/cSLC-nu/nu mice. When MDA-MB-231, A549, DU145, MIAPaCa-2, and PC-14 xenografts has reached an average volume of 100, 210, 110, 250, and 250 mm3, respectively, animals are randomized into groups of 6 mice (except for PC-14, for which groups of 3 mice are used). For oral administration, OTSSP167 and other compounds are prepared in a vehicle of 0.5% methylcellulose and given by oral garbage at the indicated dose and schedule. For intravenous administration, compounds are formulated in 5% glucose and injected into the tail vein. An administration volume of 10 mL per kg of body weight is used for both administration routes. Tumor volumes are determined every other day using a caliper.

References:
[1]. Chung S, Suzuki H, Miyamoto T, et al. Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer. Oncotarget. 2012 Dec 21. [2]. Ji W, et al. OTSSP167 Abrogates Mitotic Checkpoint through Inhibiting Multiple Mitotic Kinases. PLoS One. 2016 Apr 15;11(4):e0153518. [3]. Cho YS, et al. The crystal structure of MPK38 in complex with OTSSP167, an orally administrative MELK selective inhibitor. Biochem Biophys Res Commun. 2014 Apr 25;447(1):7-11. [4]. Li S, et al. Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in gastric cancer. Oncotarget. 2016 Feb 2;7(5):6266-80.

OTSSP167 Dilution Calculator

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OTSSP167 Molarity Calculator

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Preparing Stock Solutions of OTSSP167

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0516 mL 10.2581 mL 20.5162 mL 41.0324 mL 51.2905 mL
5 mM 0.4103 mL 2.0516 mL 4.1032 mL 8.2065 mL 10.2581 mL
10 mM 0.2052 mL 1.0258 mL 2.0516 mL 4.1032 mL 5.129 mL
50 mM 0.041 mL 0.2052 mL 0.4103 mL 0.8206 mL 1.0258 mL
100 mM 0.0205 mL 0.1026 mL 0.2052 mL 0.4103 mL 0.5129 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on OTSSP167

OTSSP167 is an inhibitor of maternal embryonic leucine zipper kinase (MELK) with IC50 value of 0.41nM [1].

MELK is a member of the AMPK serine/threonine kinase family and is involved in the mammalian embryonic development. It plays roles in cancer cell growth and formation or maintenance of cancer stem cells. OTSSP167 is a small-molecule inhibitor and can inhibit MELK’s activity effectively and selectively. OTSSP167 inhibits cell proliferation of a variety of cancer cell lines including A549, T47D, DU4475 and 22Rv1. The IC50 values are 6.7nM, 4.3nM, 2.3nM and 6nM, respectively. In mice bearing MDA-MB-231 xenograft, administration of OTSSP167 inhibits 70% tumor growth at dose of 20 mg/kg. Besides that, OTSSP167 is also found to have effects on PSMA1 and DBNL which are the novel substrates of MELK. It inhibits the phosphorylation of PSMA1 and DBNL causes the subsequent suppression of mammosphere formation [1].

References:
[1] Chung S, Suzuki H, Miyamoto T, et al. Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer. Oncotarget, 2012, 3(12): 1629.

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References on OTSSP167

MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells.[Pubmed:28214016]

Gynecol Oncol. 2017 Apr;145(1):159-166.

OBJECTIVE: Maternal embryonic leucine-zipper kinase (MELK) shows oncogenic properties in basal-like breast cancer, a cancer subtype sharing common molecular features with high-grade serous ovarian cancer. We examined the potential of MELK as a molecular and pharmacological target for treatment of epithelial ovarian cancer (EOC). METHODS/MATERIALS: Bioinformatic analysis was performed on nine OC transcriptomic data sets totaling 1241 patients. Effects of MELK depletion by shRNA or inhibition by OTSSP167 in cell lines were assessed by colony formation and MTT (proliferation) assays, Western blotting (apoptosis), and flow cytometry (cell cycle analysis). RESULTS: Elevated MELK expression was correlated with histological grading (n=6 data sets, p<0.05) and progression-free survival (HR 5.73, p<0.01) in OC patients and elevated MELK expression in other cancers with disease-free survival (n=3495, HR 1.071, p<0.001). Inhibition or depletion of MELK reduced cell proliferation and anchorage-dependent and -independent growth in various OC cell lines through a G2/M cell cycle arrest, eventually resulting in apoptosis. OTSSP167 retained its cytotoxicity in Cisplatin- and Paclitaxel-resistant IGROV1 and TYK-nu OC cells and sensitized OVCAR8 cells to Carboplatin but not Paclitaxel. CONCLUSION: MELK inhibition by OTSSP167 may thus present a strategy to treat patients with aggressive, progressive, and recurrent ovarian cancer.

The crystal structure of MPK38 in complex with OTSSP167, an orally administrative MELK selective inhibitor.[Pubmed:24657156]

Biochem Biophys Res Commun. 2014 Apr 25;447(1):7-11.

Murine protein serine/threonine kinase 38 (MPK38), also known as maternal embryonic leucine zipper kinase (MELK), has been associated with various human cancers and plays an important role in the formation of cancer stem cells. OTSSP167, a MELK selective inhibitor, exhibits a strong in vitro activity, conferring an IC50 of 0.41nM and in vivo effect on various human cancer xenograft models. Here, we report the crystal structure of MPK38 (T167E), an active mutant, in complex with OTSSP167 and describe its detailed protein-inhibitor interactions. Comparison with the previous determined structure of MELK bound to the nanomolar inhibitors shows that OTSSP167 effectively fits into the active site, thus offering an opportunity for structure-based development and optimization of MELK inhibitors.

OTSSP167 Abrogates Mitotic Checkpoint through Inhibiting Multiple Mitotic Kinases.[Pubmed:27082996]

PLoS One. 2016 Apr 15;11(4):e0153518.

OTSSP167 was recently characterized as a potent inhibitor for maternal embryonic leucine zipper kinase (MELK) and is currently tested in Phase I clinical trials for solid tumors that have not responded to other treatment. Here we report that OTSSP167 abrogates the mitotic checkpoint at concentrations used to inhibit MELK. The abrogation is not recapitulated by RNAi mediated silencing of MELK in cells. Although OTSSP167 indeed inhibits MELK, it exhibits off-target activity against Aurora B kinase in vitro and in cells. Furthermore, OTSSP167 inhibits BUB1 and Haspin kinases, reducing phosphorylation at histones H2AT120 and H3T3 and causing mislocalization of Aurora B and associated chromosomal passenger complex from the centromere/kinetochore. The results suggest that OTSSP167 may have additional mechanisms of action for cancer cell killing and caution the use of OTSSP167 as a MELK specific kinase inhibitor in biochemical and cellular assays.

Description

OTSSP167 is a highly potent MELK inhibitor with IC50 value of 0.41 nM.

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