MK-5108 (VX-689)

Catalog No.S2770

MK-5108 (VX-689) Chemical Structure

Molecular Weight(MW): 461.94

MK-5108 (VX-689) is a highly selective Aurora A inhibitor with IC50 of 0.064 nM in a cell-free assay and is 220- and 190-fold more selective for Aurora A than Aurora B/C, while it inhibits TrkA with less than 100-fold selectivity. Phase 1.

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In DMSO USD 500 In stock
USD 270 In stock
USD 370 In stock
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4 Customer Reviews

  • Effect of a selective small molecule inhibitor of AURKA on MYCN protein levels and cell viability. Western blot for MYCN protein in KNS42 cells after exposure to 0.1, 0.5 and 2.5 uM VX-689 (triangle). GAPDH is used as a loading control.

    Cancer Discov 2013 10.1158/2159-8290.CD-12-0426. MK-5108 (VX-689) purchased from Selleck.

    MK-5108 specifically inhibits AURKA and delays mitotic exit. (a) MK-5108 inhibits AURKA but not AURKB. Mitotic HeLa cells were obtained by exposure to nocodazole for 16 h followed by mechanical shake off. The cells were incubated with the indicated concentrations of MK-5108 for 2 h. Nocodazole and MG132 were included to prevent mitotic exit. Lysates were then prepared and activated phospho-AURKAThr288 and AURKBThr232 were detected with immunoblotting. Uniform loading was confirmed by immunoblotting for actin. (b) MK-5108 prevents activation of AURKA but not AURKB. HeLa cells were incubated with the indicated concentrations of MK-5108 for 8 h. Nocodazole was then added for another 6 h to trap any cells that entered mitosis. Mitotic cells were isolated by mechanical shake off. Lysates were prepared and analyzed with immunoblotting. Actin analysis was included to assess loading and transfer. (c) MK-5108 induces a G 2 /M delay. HeLa cells were treated with the indicated concentrations of MK-5108 for 24 h. DNA contents were analyzed with flow cytometry.

    Oncogene 2014 33, 3550-60. MK-5108 (VX-689) purchased from Selleck.

  • P53 expression in the 14G2a mAb-treated IMR-32 cell line and after combinatorial treatment with MK-5108 inhibitor. P53 protein content was measured in whole cell-WCE (A), cytoplasmic-CE (C) and nuclear-NE (E) extracts at 2, 6, 24 and 48 h after 14G2a addition (40 ug/ml) into culture media of IMR-32 cells, and normalized to GAPDH levels (for WCE and CE), or TBP (for NE). Mean values of three separate experiments (盨EM) obtained for the 14G2a mAb-treated cells are shown as empty bars, and calculated versus control value, set as 1 (black baseline). ANOVA shows no statistically significant changes of P53 level in time in IMR-32 WCE [F(3, 9) = 1.35, p = 0.3181]. Statistically significant changes of P53 level in time were found in CE [F(3, 6) = 53.76, p = 0.0001], and in NE [F(3, 6) = 63.17, p = 0.0001], as compared to 2 h time point. P53 expression level was measured in whole cell-WCE (B), cytoplasmic-CE (D) and nuclear-NE (F) extracts at 2 and 24 h after the 14G2a mAb treatment alone (white bars with black stripes) or in combination with MK-5108 inhibitor (black bars with white stripes), and normalized to GAPDH levels (for WCE and CE), or TBP (for NE). Below each chart representative immunoblottings are presented; C-control cells; mAb-the 14G2a mAb-treated cells; I + mAb-MK-5108 inhibitor and the mAb-treated cells. P-values for t-test were as follow: p < 0.05 (*), p < 0.01 (**), p < 0.001 (***).

    Cancer Lett 2013 341(2), 248-64. MK-5108 (VX-689) purchased from Selleck.

    HeLa cells were first synchronized to G1/S boundary with double thymidine
    procedure.  After the release of the secondary thymidine, the indicated
    concentrations of VX-689 were added to the cells for 8 hrs.  The cells were
    then treated with nocodazole to trap the mitotic cells for 4 hrs and subse-
    quently harvested by the mechanical shake off.  Cell free extracts were
    prepared and further analyzed by SDS-PAGE and western blotting with the
    indicated antibodies.  The disappearance of phospho-aurora A but not
    phospho-aurora B strongly suggested that VX-689 is a highly selective
    aurora A kinase inhibitor.

    Ken Ma Hong Kong University of Science & Technology. MK-5108 (VX-689) purchased from Selleck.

Purity & Quality Control

Choose Selective Aurora Kinase Inhibitors

Biological Activity

Description MK-5108 (VX-689) is a highly selective Aurora A inhibitor with IC50 of 0.064 nM in a cell-free assay and is 220- and 190-fold more selective for Aurora A than Aurora B/C, while it inhibits TrkA with less than 100-fold selectivity. Phase 1.
Targets
Aurora A [1]
(Cell-free assay)
0.064 nM
In vitro

MK-5108 inhibits Aurora-A activity in an ATP-competitive manner. MK-5108 shows robust selectivity against the other family kinases Aurora-B (220-fold) and Aurora-C (190-fold) in the biochemical assay. MK-5108 also reveals high selectivity for Aurora-A over other protein kinases. MK-5108 inhibits only one kinase (TrkA) with <100-fold selectivity. MK-5108 may be more Aurora-A selective than MLN8054. Consistent with the induction of pHH3-positive cells, MK-5108 induces accumulation of cells in the G2-M phase. MK-5108 inhibits the proliferation of tumor cells including HCC1143, AU565, MCF-7, HCC1806 and CAL85-1 with an IC50 of 0.42 μM, 0.45 μM, 0.52 μM, 0.56μM and 0.74 μM, respectively. [1] MK-5108 decreases cell viability in a dose-dependent fashion in all three cell lines including LEIO285, LEIO505 and SK-LSM1 cells with an IC50 of approximately 100 nM. Incubation with MK-5108 in LEIO285 increases the proportion of cells in G2/M at 48 and 72 hours post-treatment. MK-5108 significant increases in Caspase 3/7 activity when compared to DMSO-treated control cultures at both time points. In LEIO505 cells, MK-5108 leads to more cells accumulating at G2/M phases at 24 hours but not 48 hours or 72 hours. MK-5108 arrests ULMS cell lines at M phase MK-5108 decreases the IC50 of gemcitabine in LEIO285 cells, but increases IC50 of gemcitabine in LEIO505 and SK-LMS1 cells. [2]

In vivo MK-5108 induces pHH3-positive cells at doses of 16 mg/kg and 32 mg/kg. Plasma concentration of MK-5108 at 8 mg/kg and 16 mg/kg are 1.7 μM and 4.4 μM, respectively. MK-5108 treatment results in the induction of pHH3 in tumor and skin tissues, which starts at 2 hours and reachs a maximum at 4 hours. MK-5108 treatments at 15 mg/kg and 30 mg/kg results in significant tumor growth inhibition with the change in mean tumor volume for the treatment group as a percentage of the mean change in the control group (%T/C) of 10% and −6% at day 11, and 17% and 5% at day 18, respectively. MK-5108 is well tolerated at both doses, with minimal reduction in body weight. MK-5108 also exhibits significant antitumor activity through intermittent dosing in nude rats bearing SW48 tumors, MK-5108 at 15 mg/kg and 45 mg/kg causes dose-dependent tumor growth inhibition with a %T/C of 35% and 7% at day 10, and 58% and 32% at day 27, respectively. [1]

Protocol

Kinase Assay:

[1]

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Biochemical kinase assays:

Recombinant His-tagged human Aurora-A protein is expressed in Escherichia coli and is purified with HisTrap HP column. Purified recombinant human Aurora-B and Aurora-C protein are purchased. Experiments are done in quintuplicate in 96-well plates. The Aurora-A assay reaction is conducted in the presence of 20 μM ATP, 25 μM Tetra-Kemptide [RRR(GLRRASLG)4R-NH2], 1.0 μCi per well [γ-33P]-ATP, 0.1 ng per well Aurora-A in 50 mM Tris-HCl (pH 7.4), 15 mM Mg(OAc)2, and 0.2 mM EDTA at 30°C for 40 minutes. To investigate the inhibition mode of MK-5108 for Aurora-A, the IC50 values of MK-5108 are determined in the presence of different concentrations of ATP. Then, the IC50 value is plotted as a function of ATP concentration to analyze the effect of ATP concentration on the IC50 value of MK-5108. The Aurora-B assay reaction is conducted in the presence of 15 μM ATP, 100 μM Kemptide (GLRRASLG-NH2), 1.0 μCi per well [γ-33P]-ATP, 5.0 ng per well Aurora-B in 50 mM Tris-HCl (pH 7.4), 15 mM Mg(OAc)2, and 0.2 mM EDTA at 30 °C for 20 minuts. The Aurora-C assay reaction is conducted in the presence of 40 μM ATP, 100 μM Kemptide, 1.0 μCi per well [γ-33P]-ATP, 15 ng per well Aurora-C in 10 mM MOPS-NaOH (pH 7.4), 5 mM Mg(OAc)2, 1 mM (±) DTT, and 1 mM EGTA at 30 °C for 20 minutes. After kinase reactions are terminated by adding 2.0% phosphoric acid, Tetra-Kemptide or Kemptide is trapped on the MultiScreen-PH plate. Wells are washed five times with 0.64% phosphoric acid and then monitored for radioactivity in a liquid scintillation counter.
Cell Research:

[1]

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  • Cell lines: HeLa-S3 cells
  • Concentrations: 0 μM -1 μM
  • Incubation Time: 12 hours
  • Method:

    HeLa-S3 cells are synchronized at the G1-S phase boundary by double thymidine block with 2 mM thymidine. Cells are washed and seeded to 96-well cell culture plates. After 4 hours, an equal volume of medium containing MK-5108 is added to each well. Nocodazole (300 nM) is used as a 100% control. The cells are fixed overnight with cold methanol 12 hours after seeding. Then, the cells are stained with rabbit anti-phospho-histone H3 Ser28 antibody and then with anti-rabbit IgG-Cy5. Total nuclei are stained with 10 mg/mL 4,6-diamidino-2-phenylindole. Immunostained images are acquired using the IN Cell Analyzer1000 with ×10 objective lens. After acquisition of images, data are analyzed. The %pHH3-positive index is determined by measuring the %pHH3-positive cell counts per total nuclei counts for each sample, then by normalizing with respect to nocodazole-treated cells.


    (Only for Reference)
Animal Research:

[1]

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  • Animal Models: SCID mice bearing HCT116 tumors
  • Formulation: 0.5% methyl cellulose/0.24% SDS
  • Dosages: 30 mg/kg
  • Administration: Oral administration
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 92 mg/mL (199.16 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents individually and in order:
0.5% methylcellulose+0.2% Tween 80
30 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 461.94
Formula

C22H21ClFN3O3S

CAS No. 1010085-13-8
Storage powder
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00543387 Completed Cancer, Neoplasms, Tumors Merck Sharp & Dohme Corp. March 2008 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID