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.
Cited by 10 Publications
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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
|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.|
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.  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. 
|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. |
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.
|In vitro||DMSO||92 mg/mL (199.16 mM)|
|In vivo||Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
0.5% methylcellulose+0.2% Tween 80
For best results, use promptly after mixing.
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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 27 2008||Phase 1|
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