VX-680 (Tozasertib, MK-0457)

VX-680 (Tozasertib, MK-0457) is a pan-Aurora inhibitor, mostly against Aurora A with Kiapp of 0.6 nM, 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

Customer Reviews(15)

Quality Control & MSDS

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

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Product Information

  • Inhibition Profile
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  • Research Area
  • 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, 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] Aurora C [1] Aurora B [1] FLT3 [4] Bcr-Abl [4]
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]
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.
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 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.
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)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00104351 Terminated Cancer Merck Sharp & Dohme Corp. 2005-05 Phase 1
NCT00111683 Completed Chronic Myelogenous Leukemia in Blast Crisis|Lymphocytic Leukemia, B Cell, Acute|Myelodysplastic Syndromes|Myelogenous Leukemia, Chronic Merck Sharp & Dohme Corp. 2005-06 Phase 1
NCT00290550 Terminated Carcinoma, Non-Small-Cell Lung Merck Sharp & Dohme Corp. 2006-06 Phase 2
NCT00405054 Terminated Leukemia Merck Sharp & Dohme Corp. 2006-12 Phase 2
NCT00500006 Terminated Chronic Myelogenous Leukemia|Leukemia, Lymphoblastic, Acute, Philadelphia-Positive Merck Sharp & Dohme Corp. 2007-10 Phase 1

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 DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 93 mg/mL (200 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

Research Area

Customer Reviews (15)


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Rating
Source Oncogene, 2012, 31(31), 3584-96. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method Western blot analysis/ SA- β-gal staining
Cell Lines MCF7 cells
Concentrations 400 nM
Incubation Time 24-48 h
Results VX-680 on its own caused an increase in the number of senescent MCF7 cells andalso en hanced the effects of PKCι depletion on senescence induction (Figure a). VX-680, either alone or in combination with PKCι depletion, did not increase the numbers of gH2AX foci beyond those seen in controlc ells, suggesting that the two treatments promote senescence by similar mechanisms ( Figure b). VX-680 also increased the levels of p21 in MCF7 cells prior to the onset of the senescence phenotype (Figures c and d).

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Rating
Source Oncogene, 2012, 31(31), 3584-96. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method Western blot analysis/ SA- β-gal staining
Cell Lines U87MG cells
Concentrations 400 nM
Incubation Time 72/24h
Results VX -680 caused an increase in the number of senescent U87MG cells (Figure a), although only with longer (72 h) exposures to the drug. With shorter (24 h) exposures, VX-680 treatment did not produce astatistically significant increase in senescent U87MG cells, but did sensitize them to senescence inductionupon PKCι depletion (Figure b). This also occurred without any evidence for activation of the DNA -damageresponse (Figure c). VX -680 treat ment also caused an increase in p21 levels in U87MG cells, although as withsenescence induction this was only evident with longer exposures to VX-680 (Figure d).

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Rating
Source Pediatr Surg Int, 2012, 28(6), 579-89. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method Apoptosis assay
Cell Lines HUH6 cells/ HepT1 cells
Concentrations 6/12.5 μM
Incubation Time 24 h
Results Treatment with VX-680 increased the activity of Caspase-3 in a dose-dependent manner. In HUH6 cells (Fig. b) more cells with active Caspae-3 were observed at the same cell density when compared with HepT1 cells (Fig.3 a). Hence HUH6 cells show a more sensitive response to the Aurora kinase inhibitor VX-680.

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Rating
Source Pediatr Surg Int, 2012, 28(6), 579-89. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method DAPI staining and microscopy/ Western blot
Cell Lines HUH6 cells/ HepT1 cells
Concentrations 6/10 μM
Incubation Time 72 h
Results The effect of VX-680 and/or SAHA on cell morphology was similar in both, HepT1 and HUH6 cells (Fig. b). There was also a significant increase in both the nuclei and cell diameter in HepT1 cells when treated with VX–680 alone or in combination. In both HB cell. As shown in Fig. c, In both HB cell lines treatment with VX–680 and the combination with SAHA led to a decrease in histone H3 phosphorylation.

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Rating
Source Brain Pathol, 2012. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method MTT assay
Cell Lines brainstem glioma cells
Concentrations 100 nM
Incubation Time 72 h
Results VX-680 treatment of these cell lines over 72 h resulted in significant decrease in overall cell viability by 100nM for the mouse derived brainstem glioma.

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Rating
Source Brain Pathol, 2012. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method Immunofluorescent staining
Cell Lines brainstem glioma cells
Concentrations 100 nM
Incubation Time 72 h
Results Immunofluorescence staining of reversine and VX-680-treated cells for GFAP counterstained with DAPIrevealed morphological changes including irregular, large multi-nucleated cells.

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Rating
Source The Journal of Neuroscience, 2012, 32(32), 11050-11066. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method Western Blot
Cell Lines Isolated granular neurons
Concentrations 0.03 uM
Incubation Time 24 h
Results While the amounts of Aurora-A and NDEL1 were relatively unchanged, levels of phosphorylated Aurora-A and NDEL1 were significantly suppressed by Aurora-A inhibitors.

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Rating
Source Cell 2010 142, 444–455. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method Immunofluorescence Microscopy
Cell Lines HeLa cells
Concentrations
Incubation Time
Results Inhibition of Aurora kinases with VX-680 sharply reduced kinetochore-localized pT422 signal (Figure G). When normalized to the total level of CENP-E at the kinetochore (which is also reduced in VX-680 treated cells (Ditchfield et al. 2003)), a > 90% reduction in T422 phosphorylation was seen following VX-680 treatment ( Figure H).

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Rating
Source Mol Cancer Ther 2010 9, 1318–1327. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method fluorescence-activated cell sorting analysis, flow cytometry
Cell Lines BLQ1 cells, UCSF02 cells
Concentrations 0-500 nmol/L, 1-10 μmol/L
Incubation Time 24/48 h
Results As shown in Fig. B, VX-680 induced apoptosis in both BLQ1 and UCSF02 cells in a dose-dependent manner. Because Aurora kinase inhibitors were reported to cause endoreduplication and polyploidy, we measured cell cycle after a 1- and 2-day treatment with VX-680. Consistent with earlier findings in HeLa cells, treatment with 1 μmol/L VX-680 caused a marked accumulation of ALL cells with greater than 4N DNA content (Fig. C).

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Rating
Source Dr Antonino Maria Sparta ,University of Trento. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method WST-1(Roche) proliferation assay
Cell Lines SK-N-BE(2) cell lines, CHP-134 cell lines
Concentrations
Incubation Time
Results ENMD-2076 has been tested it on two different neurobiastoma cell lines(SK-N-BE(2) and CHP-134), being calculated the IC50 by a WST-1(Roche) proliferation assay, as shown in the table below. Its in vitro activity is in the micromolar range and has a comparable effect on both lines.VX-680 was used as standard, and it proved more potent on CHP-134 cells.

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Rating
Source Dr Antonino Maria Sparta ,University of Trento. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method Western blot
Cell Lines CHP-134 cells
Concentrations 1 μM
Incubation Time 24 h
Results SDS-PAGE of CHP-134 cells extracts after 24 h exposure to the indicated drug and concentration. N-myc levels were evaluated and compared to beta actin used as house-keeping protein. Aurora A blockade seems to diminish N-myc expression or stability.

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Rating
Source Dr. Zhang of Tianjin Medical University. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method Western blot
Cell Lines
Concentrations 0-10 μM
Incubation Time
Results

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Rating
Source Mol Cancer Ther 2010 9, 1318–1327. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method Western blot
Cell Lines BLQ1 (T315I mutation) cells, TXL2 (no mutation) cells
Concentrations 1-10 μmol/L
Incubation Time 24 h
Results As shown in Fig. 4, without drug treatment, the majority of Crkl protein was phosphorylated in both BLQ1 and TXL2. After exposure to increasing concentrations of VX-680 for 24 hours, Crkl shifted to its nontyrosine phos-phorylated, more rapidly migrating form but 10μ mol/L drug was required to inhibit all Crkl phosphorylation. Cotreatment with 1μmol/L VX-680 and 100 nmol/L dasatinib in TXL2 cells induced a more significant reduction in phosphotyrosine, phospho-Crk l, phospho-Stat5, and phospho-Src than treatment with either VX-680 or dasatinib alone, where as there was no significant effect of combining VX-680 with dasatinibin BLQ1 cells with the T315I mutation.

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Rating
Source Mol Cancer Ther 2010 9, 1318–1327. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method Giemsa staining, flow cytometry
Cell Lines BLQ1 cells, BLQ1-VX-Tx cells
Concentrations 1/1.5 μmol/L, 5nmol/L
Incubation Time 72 h
Results As shown in Fig. A (top left), after 3 days of VX-680 exposure, viability of the cells decreased to 40%-50%. After removal of the drug, viability of the culture began to gradually increase. Cell cycle analysis indicated that although we removed VX-680, a subpopulation of BLQ1 cells was still arrested, with more than 4N DNA content (37%), compared with cells untreated with VX-680 (22.8%). On day 21, we compared BLQ1 cells that had never been VX-680 treated with those that had been exposed to the drug 21 days before (BLQ1-VX-Tx). Remarkably, compared with the control cells, a sub-population of the VX-680-treated BLQ1 cells was much larger (Fig. B) than the original cells. We then compared the sensitivity of BLQ1 and BLQ1-VX -Tx to treatment with VX-680. We found that BLQ1-VX-Tx cells were still sensitive to VX-680 (Fig. C)

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Rating
Source Mol Cancer Ther 2010 9, 1318–1327. VX-680 (Tozasertib, MK-0457) purchased from Selleck
Method trypan blue exclusion test/flow cytometry
Cell Lines TXL2 cells, UCSF02 cells
Concentrations 1 μmol/L
Incubation Time 24-72 h
Results As shown in Fig. A, cotreatment with 1 μmol/L VX-680 and 100 nmol/L dasatinib caused an impressive 80% decrease in viability, where as treatment with 1 μmol/L VX-680 or 100 nmol/L dasatinib alone only caused a 40% drop in viability in TXL2 cells over a period of 72 hours ( P < 0.001). Similar effects were observed in UCSF02 cells. We also evaluated the combined effects of VX-680 and dasatinib on apoptosis and cell cycle progression. Consistent with the results of the viability assay, cotreat ment with VX -680 and dasatinib in duced significantly more cells to undergo apoptosis than treatment with a single drug(Fig. B). As shown in Fig. C, V X-680 treatment caused accumulation of cells with a greater than 4N DNA content. Compared with treatment with either drug alone, an increase in the numbers of cells with less than N DNA content was seen at 48 hours. Together, these results show that VX-680 and dasatinib synergize to induce cytotoxic activities.

Product Citations (26)

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