VX-680 (Tozasertib, MK-0457)

Catalog No.S1048

VX-680 (Tozasertib, MK-0457) is a pan-Aurora inhibitor, mostly against Aurora A with Kiapp of 0.6 nM in a cell-free assay, less potent towards Aurora B/Aurora C and 100-fold more selective for Aurora A than 55 other kinases. Phase 2.

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VX-680 (Tozasertib, MK-0457) Chemical Structure

VX-680 (Tozasertib, MK-0457) Chemical Structure
Molecular Weight: 464.59

Validation & Quality Control

Cited by 35 publications:

15 customer reviews :

Quality Control & MSDS

Related Compound Libraries

VX-680 (Tozasertib, MK-0457) is available in the following compound libraries:

Aurora Kinase Inhibitors with Unique Features

  • Pan Aurora Kinase Inhibitors

    Danusertib (PHA-739358) Pan-Aurora kinase inhibitor, Aurora A/B/C, IC50=13 nM/79 nM/61 nM. SNS-314 Mesylate Pan-Aurora kinase inhibitor, Aurora A/B/C, IC50=9 nM/31 nM/3 nM.

  • Most Potent Aurora Kinase Inhibitor

    MK-5108 (VX-689) Aurora A, IC50=0.064 nM.

  • Aurora Kinase Inhibitor in Clinical Trial

    Alisertib (MLN8237) Phase III for Relapsed/Refractory Peripheral T-Cell Lymphoma.

  • Classic Aurora Kinase Inhibitor

    Hesperadin Potently inhibits Aurora B with IC50 of 250 nM.

Product Information

  • Compare Aurora Kinase Inhibitors
    Compare Aurora Kinase Products
  • Research Area
  • Inhibition Profile
  • VX-680 (Tozasertib, MK-0457) Mechanism

Product Description

Biological Activity

Description VX-680 (Tozasertib, MK-0457) is a pan-Aurora inhibitor, mostly against Aurora A with Kiapp of 0.6 nM in a cell-free assay, less potent towards Aurora B/Aurora C and 100-fold more selective for Aurora A than 55 other kinases. Phase 2.
Targets Aurora A [1]
(Cell-free assay)
Aurora C [1]
(Cell-free assay)
Aurora B [1]
(Cell-free assay)
FLT3 [4]
(Cell-free assay)
Bcr-Abl [4]
(Cell-free assay)
IC50 0.6 nM(Ki app) 4.6 nM(Ki app) 18 nM(Ki app) 30 nM(Ki) 30 nM(Ki)
In vitro Although its multi-kinase profile, VX-680 induces similar cytotoxicity with IC50 of approximately 300 nM and exhibits an AUR B-like inhibitory phenotype of G2/M arrest, endoreduplication and apoptosis in BaF3 cells transfected with ABL or FLT-3 (mutant and wild type) kinases. VX-680 prevents the CAL-62 proliferation in a time-dependent manner. VX-680 treatment for 14 days significantly decreases the number and size of colonies by approximately 70% in the 8305C and 90% in the CAL-62, 8505C and BHT-101. Treatment of the different ATC cells with VX-680 inhibits proliferation with the IC50 between 25 and 150  nM. The VX-680 significantly impairs the ability of the different cell lines to form colonies in soft agar. Analysis of caspase-3 activity indicates that VX-680 induces apoptosis in the different cell lines. CAL-62 cells exposed for 12  hours to VX-680 showed an accumulation of cells with ≥4N DNA content. Time-lapse analysis demonstrates that VX-680-treated CAL-62 cells exit metaphase without dividing. Moreover, histone H3 phosphorylation is abrogated following VX-680 treatment. [2] VX-680 has significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples. [3]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
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... Click to View More Cell Line Experimental Data

In vivo VX-680 gives rise to a marked decrease in tumor size in a human AML (HL-60) xenograft model. In mude mice treateed with VX-680 at 75 mg/kg, twice a day intraperitoneally (b.i.d. i.p.) for 13 days, mean tumor volumes are reduced by 98%. Tumor growth decrease is dose dependent and significant at a dose of 12.5 mg/kg b.i.d. VX-680 is well tolerated, with a small decrease in body weight observed only at the highest dose. VX-680 also triggers tumor regresson in pancreatic and colon xenograft models. VX-680 also displays potent antitumor activity when infused i.v. in mude rats bearing established HCT116 tumors. A higher dose of VX-680 (2 mg/kg/h) improves efficacy with a 56% decrease in mean tumor volume. [1]
Features

Protocol(Only for Reference)

Kinase Assay:

[3]

Kinase inhibition assays The consumption of ATP is coupled via the pyruvate kinase/lactic dehydrogenase enzyme pair to the oxidation of NADH, which can be monitored through the decrease in absorption at 340 nm. Reactions contains 100 mM Tris (pH 8), 10 mM MgCl2, 2.2 mM ATP, 1 mM phosphoenolpyruvate, 0.6 mg/mL NADH, 75 units/mL pyruvate kinase, 105 units/mL lactate dehydrogenase, and 0.5 mM substrate peptide (sequence: EAIYAAPFAKKK). Reactions (75 μL) are started by adding sufficient kinase to bring the reactions to 30 nM kinase concentration and the decrease in absorbance is monitored over 30 minutes at 30°C in a microtiter plate spectrophotometer. Inhibitory constants are obtained through addition of 3.75 μL VX-680 in 100% DMSO or DMSO alone. Ki values are calculated as follows, K i = IC50 / (1 + [S]/Kd), where [S] = [ATP] = 2.2 mM, and Kd (of ATP to Abl) = 70 μM. These values are calculated assuming a Kd (ATP) of 70 μM for wild type and H396P Abl kinase domain.

Cell Assay:

[2]

Cell lines CAL-62 cells
Concentrations 5-500 nM
Incubation Time 4 days
Method

The CAL-62 cells are cultured in the absence (dimethyl sulfoxide, DMSO) or the presence of 500  nM VX-680 for different periods of time (1-5 days). The dose-dependent effects of VX-680 on cell proliferation are evaluated by treating the different ATC cells for 4 days with different concentrations of the Aurora inhibitor (5–500  nM). The cells are pulse labeled with 30  mM BrdU for 2  hours before the end of the incubation time. The BrdU incorporation is analyzed by means of a colorimetric immunoassay using the cell proliferation ELISA kit. The results from VX-680-treated cells are compared with those observed in control cells and expressed as a fold of variation versus control.

Animal Study:

[1]

Animal Models Female athymic NCr-nu mice bearing HL-60 leukemia cells
Formulation 50% PEG300 in 50 mM phosphate buffer
Dosages 50 mg/kg, 75 mg/kg
Administration Administered via i.p.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Harrington EA, et al. Nat Med. 2004, 10(3), 262-267.

[2] Arlot-Bonnemains Y, et al. Endocr Relat Cancer. 2008, 15(2), 559-568.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00500006 Terminated Chronic Myelogenous Leukemia|Leukemia, Lymphoblastic, Acute, Philadelphia-Positive Merck Sharp & Dohme Corp. October 2007 Phase 1
NCT00405054 Terminated Leukemia Merck Sharp & Dohme Corp. December 2006 Phase 2
NCT00290550 Terminated Carcinoma, Non-Small-Cell Lung Merck Sharp & Dohme Corp. June 2006 Phase 2
NCT00111683 Completed Chronic Myelogenous Leukemia in Blast Crisis|Lymphocytic Leukemia, B Cell, Acute|Myelodysplastic Syndromes|Myelogenous Leukemia, Chronic Merck Sharp & Dohme Corp. June 2005 Phase 1
NCT02532868 Terminated Cancer Merck Sharp & Dohme Corp. May 2005 Phase 1

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Chemical Information

Download VX-680 (Tozasertib, MK-0457) SDF
Molecular Weight (MW) 464.59
Formula

C23H28N8OS

CAS No. 639089-54-6
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 93 mg/mL (200.17 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* 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 Name N-(4-(4-(5-methyl-1H-pyrazol-3-ylamino)-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

If you have any other enquiries, please leave a message.

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