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639089-54-6 molecular structure
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N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide

ChemBase ID: 72479
Molecular Formular: C23H28N8OS
Molecular Mass: 464.58642
Monoisotopic Mass: 464.21067856
SMILES and InChIs

SMILES:
c1(cc(nc(n1)Sc1ccc(cc1)NC(=O)C1CC1)N1CCN(CC1)C)Nc1cc([nH]n1)C
Canonical SMILES:
CN1CCN(CC1)c1nc(Sc2ccc(cc2)NC(=O)C2CC2)nc(c1)Nc1n[nH]c(c1)C
InChI:
InChI=1S/C23H28N8OS/c1-15-13-20(29-28-15)25-19-14-21(31-11-9-30(2)10-12-31)27-23(26-19)33-18-7-5-17(6-8-18)24-22(32)16-3-4-16/h5-8,13-14,16H,3-4,9-12H2,1-2H3,(H,24,32)(H2,25,26,27,28,29)
InChIKey:
GCIKSSRWRFVXBI-UHFFFAOYSA-N

Cite this record

CBID:72479 http://www.chembase.cn/molecule-72479.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide
IUPAC Traditional name
N-[4-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide
Synonyms
N-[4-[[4-(4-Methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide
VX 680
MK 0457
Tozasertib
MK-0457
Tozasertib
VX-680
CAS Number
639089-54-6
PubChem SID
162037404
PubChem CID
5494449

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID
PubChem 5494449 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 11.981596  H Acceptors
H Donor LogD (pH = 5.5) 2.7797399 
LogD (pH = 7.4) 4.3690386  Log P 4.616985 
Molar Refractivity 136.3571 cm3 Polarizability 49.464108 Å3
Polar Surface Area 102.07 Å2 Rotatable Bonds
Lipinski's Rule of Five true 

PROPERTIES

PROPERTIES

Physical Property Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Solubility
DMSO expand Show data source
Methanol expand Show data source
Apperance
White Solid expand Show data source
Melting Point
248-253°C expand Show data source
Storage Condition
-20°C expand Show data source
-20°C Freezer expand Show data source
MSDS Link
Download expand Show data source
Target
Aurora Kinase expand Show data source
Salt Data
Free Base expand Show data source
Certificate of Analysis
Download expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals TRC TRC
Selleck Chemicals - S1048 external link
Research Area
Description Cancer
Biological Activity
Description VX-680 (MK-0457, Tozasertib) is a pan-Aurora inhibitor of Aurora A, Aurora B and Aurora C with Kiapp of 0.6 nM, 18 nM and 4.6 nM, respectively.
Targets

Aurora A

Aurora B

Aurora C

IC50

0.6 nM (Kiapp)

18 nM (Kiapp)

4.6 nM (Kiapp)

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]
Clinical Trials A phase II clinical trial of VX-680 has been terminated in the treatment of non-small-cell lung.
Features
Protocol
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
Methods

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
Doses 50 mg/kg, 75 mg/kg
Administration Administered via i.p.
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.
[3] Young MA, et al. Cancer Res. 2006, 66(2), 1007-1014.
Toronto Research Chemicals - T700000 external link
A multikinase inhibitor once used for cancer treatment.

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