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MK-5108

Cat. No. M3516
MK-5108 Structure
Synonym:

VX-689

Size Price Availability Quantity
5mg USD 210 In stock
10mg USD 300 In stock
50mg USD 820 In stock
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Quality Control
  • Current batch:
  • Purity >99%
  • COA
  • MSDS
Biological Activity

MK-5108 (VX-689) is a highly selective aurora-A kinase inhibitor with an IC50 of 0.064 nM. 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. 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 elevates IC50 of gemcitabine in LEIO505 and SK-LMS1 cells. 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. Although MK-5108 alone reveals little antitumor activity, the combination of MK-5108 with docetaxel displays greater antitumor activity: %T/C of −42% and −28% at day 6 and day 10, respectively. In the ES-2 tumor, the combination of MK-5108 and docetaxel is also more effective than either agent alone. MK-5108 has been completed in a phase I clinical trial for the treatment of advanced solid tumors.

Protocol
Cell Experiment
Cell lines HeLa-S3 cells
Preparation method Synchronizing HeLa-S3 cells at the G1-S phase boundary by double thymidine block with 2 mM thymidine. Washing cells and seeding to 96-well cell culture plates. 4 hours later , an equal volume of medium containing MK-5108 is added to each well. Nocodazole (300 nM) is used as a 100% control. Fixing the cells overnight with cold methanol 12 hours after seeding. Then, staining the cells with rabbit anti-phospho-histone H3 Ser28 antibody and then with anti-rabbit IgG-Cy5. Staining total nucleiwith 10 mg/mL 4′,6-diamidino-2-phenylindole. Using the IN Cell Analyzer1000 with ×10 objective lens to acquire Immunostained images . 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.
Concentrations 0 μM -1 μM
Incubation time 12 hours
Animal Experiment
Animal models SCID mice bearing HCT116 tumors
Formulation 0.5% methyl cellulose/0.24% SDS
Dosages 30 mg/kg
Administration Oral administration
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 461.94
Formula C22H21ClFN3O3S
CAS Number 1010085-13-8
Purity >99%
Solubility DMSO 90 mg/mL
Storage at -20°C
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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: MK-5108, VX-689 supplier, Aurora Kinase, inhibitors

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