VX-680 (MK-0457,Tozasertib)Aurora kinase inhibitor CAS# 639089-54-6 |
2D Structure
- Ivacaftor hydrate
Catalog No.:BCC1664
CAS No.:1134822-07-3
- Ivacaftor benzenesulfonate
Catalog No.:BCC1663
CAS No.:1134822-09-5
- PTC124 (Ataluren)
Catalog No.:BCC3881
CAS No.:775304-57-9
- Ivacaftor (VX-770)
Catalog No.:BCC2478
CAS No.:873054-44-5
- VX-809
Catalog No.:BCC3712
CAS No.:936727-05-8
Quality Control & MSDS
3D structure
Package In Stock
Number of papers citing our products
Cas No. | 639089-54-6 | SDF | Download SDF |
PubChem ID | 5494449 | Appearance | Powder |
Formula | C23H28N8OS | M.Wt | 464.59 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Synonyms | MK 0457, Tozasertib | ||
Solubility | DMSO : ≥ 106.67 mg/mL (229.60 mM) *"≥" means soluble, but saturation unknown. | ||
Chemical Name | N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide | ||
SMILES | CC1=CC(=NN1)NC2=NC(=NC(=C2)N3CCN(CC3)C)SC4=CC=C(C=C4)NC(=O)C5CC5 | ||
Standard InChIKey | GCIKSSRWRFVXBI-UHFFFAOYSA-N | ||
Standard 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) | ||
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. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
||
About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
||
Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. |
Description | High affinity and selective Aurora kinase inhibitor (Ki values are 0.6, 5 and 18 nM for Aurora A, Aurora C and Aurora B, respectively). Also exhibits affinity for FLT-3 and Abl. Exhibits selectivity for Aurora kinase over 190 other protein kinases. Inhibits proliferation and induces apoptosis in a number of cancer cell lines in vitro. Reduces tumor size in leukemia and colon cancer cell xenografts in mice. |
VX-680 (MK-0457,Tozasertib) Dilution Calculator
VX-680 (MK-0457,Tozasertib) Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 2.1524 mL | 10.7622 mL | 21.5244 mL | 43.0487 mL | 53.8109 mL |
5 mM | 0.4305 mL | 2.1524 mL | 4.3049 mL | 8.6097 mL | 10.7622 mL |
10 mM | 0.2152 mL | 1.0762 mL | 2.1524 mL | 4.3049 mL | 5.3811 mL |
50 mM | 0.043 mL | 0.2152 mL | 0.4305 mL | 0.861 mL | 1.0762 mL |
100 mM | 0.0215 mL | 0.1076 mL | 0.2152 mL | 0.4305 mL | 0.5381 mL |
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. |
Calcutta University
University of Minnesota
University of Maryland School of Medicine
University of Illinois at Chicago
The Ohio State University
University of Zurich
Harvard University
Colorado State University
Auburn University
Yale University
Worcester Polytechnic Institute
Washington State University
Stanford University
University of Leipzig
Universidade da Beira Interior
The Institute of Cancer Research
Heidelberg University
University of Amsterdam
University of Auckland
TsingHua University
The University of Michigan
Miami University
DRURY University
Jilin University
Fudan University
Wuhan University
Sun Yat-sen University
Universite de Paris
Deemed University
Auckland University
The University of Tokyo
Korea University
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
- VUF 5681 dihydrobromide
Catalog No.:BCC7383
CAS No.:639089-06-8
- LH846
Catalog No.:BCC4246
CAS No.:639052-78-1
- Zinc Phytate
Catalog No.:BCN8302
CAS No.:63903-51-5
- Pinoresinol diglucoside
Catalog No.:BCN1093
CAS No.:63902-38-5
- Akuammidine
Catalog No.:BCN6509
CAS No.:639-36-1
- Ajmalidine
Catalog No.:BCN3491
CAS No.:639-30-5
- Gypsogenin
Catalog No.:BCC8993
CAS No.:639-14-5
- Cloxyfonac
Catalog No.:BCC5473
CAS No.:6386-63-6
- Meclofenamate Sodium
Catalog No.:BCC5490
CAS No.:6385-02-0
- NMDA (N-Methyl-D-aspartic acid)
Catalog No.:BCC4590
CAS No.:6384-92-5
- H-Glu-OMe
Catalog No.:BCC2924
CAS No.:6384-08-3
- Phyllostadimer A
Catalog No.:BCN4178
CAS No.:638203-32-4
- (3R,10S)-Heptadeca-1,8-diene-4,6-diyne-3,10-diol
Catalog No.:BCC9111
CAS No.:63910-76-9
- Artemisinin
Catalog No.:BCN5814
CAS No.:63968-64-9
- Hopeyhopin
Catalog No.:BCN7533
CAS No.:63975-56-4
- 13-Oxopodocarp-8(14)-en-18-oic acid
Catalog No.:BCN4009
CAS No.:63976-69-2
- Lobeline Hydrochloride
Catalog No.:BCC8202
CAS No.:63990-84-1
- Physostigmine hemisulfate
Catalog No.:BCC6724
CAS No.:64-47-1
- Demeclocycline hydrochloride
Catalog No.:BCC5303
CAS No.:64-73-3
- Tetracycline Hydrochloride
Catalog No.:BCC1206
CAS No.:64-75-5
- Tolbutamide
Catalog No.:BCC5001
CAS No.:64-77-7
- Colchicine
Catalog No.:BCN6271
CAS No.:64-86-8
- Etimizol
Catalog No.:BCC1562
CAS No.:64-99-3
- H-D-Val-OH
Catalog No.:BCC3145
CAS No.:640-68-6
Inhibition of AURKA kinase activity suppresses collective invasion in a microfluidic cell culture platform.[Pubmed:28592839]
Sci Rep. 2017 Jun 7;7(1):2973.
Tumor local invasion is the first step of metastasis cascade which remains the key obstacle for cancer therapy. Collective cell migration plays a critical role in tumor invading into surrounding tissues. In vitro assays fail to assess collective invasion in a real time manner. Herein we aim to develop a three-dimensional (3D) microfluidic cell invasion model to determine the dynamic process. In this model, collective invasion of breast cancer cells is induced by the concentration gradient of fetal bovine serum. We find that breast cancer cells adopt a collective movement rather than a random manner when the cells invade into extracellular matrix. The leading cells in the collective movement exhibit an increased expression of an Aurora kinase family protein - AURKA compared with the follower cells. Inhibition of AURKA kinase activity by VX680 or AKI603 significantly reduces the phosphorylation of ERK1/2 (Thr202/Tyr204) and collective cohort formation. Together, our study illustrates that AURKA acts as a potential therapeutic target for suppressing the process of tumor collective invasion. The 3D microfluidic cell invasion model is a reliable, measurable and dynamic platform for exploring potential drugs to inhibit tumor collective invasion.
Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons.[Pubmed:28641113]
Neuron. 2017 Jun 21;94(6):1142-1154.e6.
Dual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole-genome, small interfering RNA libraries. Explaining why DLK inhibition is only partially protective, we identify leucine zipper kinase (LZK) as cooperating with DLK to activate downstream signaling and cell death in RGCs, including in a mouse model of optic nerve injury, and show that the same pathway is active in human stem cell-derived RGCs. Moreover, we identify four transcription factors, JUN, activating transcription factor 2 (ATF2), myocyte-specific enhancer factor 2A (MEF2A), and SRY-Box 11 (SOX11), as being the major downstream mediators through which DLK/LZK activation leads to RGC cell death. Increased understanding of the DLK pathway has implications for understanding and treating neurodegenerative diseases.
Functional Effects of AKT3 on Aurora Kinase Inhibitor-induced Aneuploidy.[Pubmed:28028179]
J Biol Chem. 2017 Feb 3;292(5):1910-1924.
The suppression of mitotic Aurora kinases (AURKs) by AURK inhibitors frequently causes cytokinetic failure, leading to polyploidy or aneuploidy, indicating the critical role of AURK-mediated phosphorylation during cytokinesis. We demonstrate the deregulated expression of AKT3 in Aurora kinase inhibitor (AURKi)-resistant cells, which we established from human colorectal cancer HCT 116 cells. The AKT family, which includes AKT1, -2, and -3, plays multiple roles in antiapoptotic functions and drug resistance and is involved in cell growth and survival pathways. We found that an AKT inhibitor, AZD5363, showed synergistic effect with an AURKi, VX-680, on two AKT3-expressing AURKi-resistant cell lines, and AKT3 knockdown sensitized cells to VX-680. Consistent with these activities, AKT3 expression suppressed AURKi-induced apoptosis and conferred resistance to AURKi. Thus, AKT3 expression affects cell sensitivity to AURKi. Moreover, we found that AKT3 expression suppressed AURKi-induced aneuploidy, and inversely AKT3 knockdown enhanced it. In addition, partial co-localization of AKT3 with AURKB was observed during anaphase. Overall, this study suggests that AKT3 could repress the antiproliferative effects of AURKi, with a novel activity particularly suppressing the aneuploidy induction.
A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation.[Pubmed:28182563]
Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14366-14371.
X-chromosome inactivation is a mechanism of dosage compensation in which one of the two X chromosomes in female mammals is transcriptionally silenced. Once established, silencing of the inactive X (Xi) is robust and difficult to reverse pharmacologically. However, the Xi is a reservoir of >1,000 functional genes that could be potentially tapped to treat X-linked disease. To identify compounds that could reactivate the Xi, here we screened approximately 367,000 small molecules in an automated high-content screen using an Xi-linked GFP reporter in mouse fibroblasts. Given the robust nature of silencing, we sensitized the screen by "priming" cells with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5azadC). Compounds that elicited GFP activity include VX680, MLN8237, and 5azadC, which are known to target the Aurora kinase and DNA methylation pathways. We demonstrate that the combinations of VX680 and 5azadC, as well as MLN8237 and 5azadC, synergistically up-regulate genes on the Xi. Thus, our work identifies a synergism between the DNA methylation and Aurora kinase pathways as being one of interest for possible pharmacological reactivation of the Xi.
Identification of human flavin-containing monooxygenase 3 substrates by a colorimetric screening assay.[Pubmed:28137602]
Anal Biochem. 2017 Apr 1;522:46-52.
Human hepatic flavin-containing monooxygenase 3 is a phase I drug-metabolizing enzyme that is responsible for the oxidation of a variety of drugs and xenobiotics. This work reports on a high throughput rapid colorimetric assay for the screening of substrates or inhibitors of this enzyme. The method is based on the competition of two substrates for access to the active site of hFMO3 whereby the enzymatic product of the first drug converts nitro-5-thiobenzoate (TNB, yellow) to 5,5'-dithiobis (2-nitrobenzoate) (DTNB, colourless). Upon addition of a competing substrate, the amount of detected DNTB is decreased. The assay is validated testing three known substrates of hFMO3, namely benzydamine, tozasertib and tamoxifen. The latter drugs resulted in 41%-55% inhibition. In addition, two other drugs also classified as doping drugs, selegiline and clomiphene, were selected based on their chemical structure similarity to known substrates of hFMO3. These drugs showed 21% and 60% inhibition in the colorimetric assay and therefore were proven to be hFMO3 substrates. LC-MS was used to confirm their N-oxide products. Further characterisation of these newly identified hFMO3 substrates was performed determining their Km and kcat values that resulted to be 314 muM and 1.4 min(-1) for selegiline and, 18 muM and 0.1 min(-1) for clomiphene. This method paves the way for a rapid automated high throughput screening of nitrogen-containing compounds as substrates/inhibitors of hFMO3.
The discovery of the potent aurora inhibitor MK-0457 (VX-680).[Pubmed:19447622]
Bioorg Med Chem Lett. 2009 Jul 1;19(13):3586-92.
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) containing the T315I mutation.
VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.[Pubmed:14981513]
Nat Med. 2004 Mar;10(3):262-7.
The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumors, and lead to aneuploidy and tumorigenesis. Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. This compound causes profound inhibition of tumor growth in a variety of in vivo xenograft models, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses. Our data indicate that Aurora kinase inhibition provides a new approach for the treatment of multiple human malignancies.