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VX-680 (MK-0457,Tozasertib)Aurora kinase inhibitor

VX-680 (MK-0457,Tozasertib)

Catalog No. A4111
Size Price Stock Qty
10mM (in 1mL DMSO) $65.00 In stock
50mg $60.00 In stock
100mg $100.00 In stock
250mg $200.00 In stock

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Sample solution is provided at 25 µL, 10mM.

Quality Control

Quality Control & MSDS

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Chemical structure

VX-680 (MK-0457,Tozasertib)

Biological Activity

Description VX-680 is an inhibitor of Aurora with Ki values of 0.6 nM, 4.6 nM, 18 nM, 30 nM and 30 nM for Aurora A, C, B, FLT3 and Bcr-Abl, respectively.
Targets Aurora A Aurora B Aurora C FLT3 Bcr-Abl  
IC50 0.6 nM (Ki) 4.6 nM (Ki) 18 nM (Ki) 30 nM (Ki) 30 nM (Ki)  

Protocol

Kinase experiment [1]:

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 contained 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) were started by adding sufficient kinase to bring the reactions to 30 nM kinase concentration and the decrease in absorbance was monitored over 30 mins at 30 °C in a microtiter plate spectrophotometer. Inhibitory constants were obtained through addition of 3.75 μL VX-680 in 100% DMSO or DMSO alone. Ki values were calculated as follows, Ki = IC50 / (1 + [S]/Kd), where [S] = [ATP] = 2.2 mM, and Kd (of ATP to Abl) = 70 μM. These values were calculated assuming a Kd (ATP) of 70 μM for wild type and H396P Abl kinase domain.

Cell experiment [2]:

Cell lines

CAL-62 cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months.

Reacting condition

5 ~ 500 nM; 4 days

Applications

VX-680 prevented the CAL-62 proliferation in a time-dependent manner.

Animal experiment [3]:

Animal models

Female athymic NCr-nu mice bearing HL-60 leukemia cells

Dosage form

12.5, 25, 50 or 70 mg/kg; i.p.; b.i.d., for 13 days

Applications

In female athymic NCr-nu mice bearing HL-60 leukemia cells, VX-680 (70 mg/kg; i.p.; b.i.d., for 13 days) reduced the tumor volume by 98%.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Young MA, Shah NP, Chao LH, Seeliger M, Milanov ZV, Biggs WH 3rd, Treiber DK, Patel HK, Zarrinkar PP, Lockhart DJ, Sawyers CL, Kuriyan J. Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res. 2006 Jan 15;66(2):1007-14.

[2]. Arlot-Bonnemains Y, Baldini E, Martin B, Delcros JG, Toller M, Curcio F, Ambesi-Impiombato FS, D'Armiento M, Ulisse S. Effects of the Aurora kinase inhibitor VX-680 on anaplastic thyroid cancer-derived cell lines. Endocr Relat Cancer. 2008 Jun;15(2):559-68.

[3]. Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, Graham JA, Demur C, Hercend T, Diu-Hercend A, Su M, Golec JM, Miller KM. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med. 2004 Mar;10(3):262-7. Epub 2004 Feb 22.

VX-680 (MK-0457,Tozasertib) Dilution Calculator

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Chemical Properties

Cas No. 639089-54-6 SDF Download SDF
Chemical Name N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide
Canonical SMILES CC1=CC(=NN1)NC2=NC(=NC(=C2)N3CCN(CC3)C)SC4=CC=C(C=C4)NC(=O)C5CC5
Formula C23H28N8OS M.Wt 464.59
Solubility Soluble in DMSO > 10 mM Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

Background

VX-680 (also known as MK-0457 or tozasertib), discovered through a molecular screening campaign, is a potent inhibitor of pan-aurora kinase as well as other kinases including Src, GSK3β, Flt3, JAK2, BCR-Abl (wild type) and BCR-Abl (T315I mutant). It binds to the inactive conformations of non-aurora kinases preventing activation, which leads to the inhibition of a wide array of kinases. Having been extensively investigated in cell lines and/or xenografts in animal models, VX-680 exhibits high degree of anti-tumor activity against a broad spectrum of tumor types, including ovarian, renal cell carcinoma, thyroid, oral squamous cell, CML (wild-type and mutant BCR-Abl), AML, and MM.

Reference

Myke R. Green, Joseph E. Woolery, and Daruka Mahadevan. Update on aurora kinase targeted therapeutics in oncology. Expert Opin Drug Discov. 2011; 6(3): 291-307