GW843682X

PLK1/PLK3 inhibitor,potent and selective CAS# 660868-91-7

GW843682X

Catalog No. BCC1614----Order now to get a substantial discount!

Product Name & Size Price Stock
GW843682X:5mg $91.00 In stock
GW843682X:10mg $155.00 In stock
GW843682X:25mg $364.00 In stock
GW843682X:50mg $637.00 In stock
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Chemical structure

GW843682X

3D structure

Chemical Properties of GW843682X

Cas No. 660868-91-7 SDF Download SDF
PubChem ID 9826308 Appearance Powder
Formula C22H18F3N3O4S M.Wt 477.46
Type of Compound N/A Storage Desiccate at -20°C
Synonyms GW843682
Solubility DMSO : 33.33 mg/mL (69.81 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 5-(5,6-dimethoxybenzimidazol-1-yl)-3-[[2-(trifluoromethyl)phenyl]methoxy]thiophene-2-carboxamide
SMILES COC1=C(C=C2C(=C1)N=CN2C3=CC(=C(S3)C(=O)N)OCC4=CC=CC=C4C(F)(F)F)OC
Standard InChIKey JSKUWFIZUALZLX-UHFFFAOYSA-N
Standard InChI InChI=1S/C22H18F3N3O4S/c1-30-16-7-14-15(8-17(16)31-2)28(11-27-14)19-9-18(20(33-19)21(26)29)32-10-12-5-3-4-6-13(12)22(23,24)25/h3-9,11H,10H2,1-2H3,(H2,26,29)
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.

Biological Activity of GW843682X

DescriptionSelective inhibitor of polo-like kinase 1 (PLK1) and polo-like kinase 3 (PLK3) (IC50 values are 2.2 and 9.1 nM respectively). Displays > 100-fold selectivity over ~30 other kinases tested including cdk1 and cdk2. Inhibits proliferation of most tumor cells in vitro and is selective over normal diploid fibroblasts.

Protocol

Kinase Assay [1]
PLK1 and PLK3 proteins are prepared from baculovirus-infected Trichoplusia ni cells. Enzyme activity for PLK1 and PLK3 is determined as follows. All measurements are obtained under conditions where signal production increased linearly with time and enzyme. Test compounds are added to white 384-well assay plates (0.1 μL for 10 μL and some 20 μL assays, 1 μL for some 20 μL assays) at variable known concentrations in 100% DMSO. DMSO (1-5% final) and EDTA (65 mM) are used as controls. Reaction Mix containes the following components at 22°C: 25 mM HEPES (pH 7.2); 15 mM MgCl2; 1 μM ATP; 0.05 μCi/well [γ-33P]ATP (10 Ci/mmol); 1 μM substrate peptide (Biotin-Ahx-SFNDTLDFD); 0.15 mg/mL bovine serum albumin; 1 mM DTT; and 2 nM PLK1 kinase domain or 5 nM full-length PLK3. Reaction Mix (10 or 20 μL) is quickly added to each well immediately following addition of enzyme via automated liquid handlers and incubated for 1 to 1.5 h at 22°C. The 20 μL enzymatic reactions are stopped with 50 μL of stop mix [50 mM EDTA, 4.0 mg/mL streptavidin SPA beads in Dulbecco's PBS (without Mg2+ and Ca2+), 50 μM ATP] per well. The 10 μL reactions are stopped with 10 μL of stop mix [50 mM EDTA, 3.0 mg/mL streptavidin-coupled SPA Imaging Beadsin Dulbecco's PBS (without Mg2+ and Ca2+), 50 μM ATP] per well. Plates are sealed, spun at 500 × g for 1 min or settled overnight, and counted in Packard TopCount for 30 s/well or imaged with a Viewlux imager. Signal above background (EDTA controls) is converted to percent inhibition relative to that obtained in control (DMSO-only) wells[1].

Cell Assay [1]
Assays are carried out and data analyzed. In these assays, H460 cells are plated at a density of 2,000 per well, HDF cells are plated at 5,000 per well, and the drug-resistant cell line MES-SA/DX5 and its sensitive parent line MES-SA are plated at 7,000 and 6,000 per well, respectively, in a 96-well plate. These densities allowed vehicle controls to grow logarithmically during the course of the 3-day assay. All cells are exposed to 3-fold dilutions of the compound (30-0.00152 μM) in low-glucose DMEM containing 5% FBS, 50 μg/mL gentamicin, and 0.3% (v/v) DMSO (HDF cells); RPMI 1640 containing 5% FBS, 50 μg/mL gentamicin, and 0.3% (v/v) DMSO (H460); or McCoy's 5A containing 5% FBS, 50 μg/mL gentamicin, and 0.3% (v/v) DMSO (MES-SA and MES-SA/DX5)[1].

References:
[1]. Lansing TJ, et al. In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1. Mol Cancer Ther. 2007 Feb;6(2):450-9. Epub 2007 Jan 31. [2]. Didier C, et al. Evaluation of Polo-like Kinase 1 inhibition on the G2/M checkpoint in Acute Myelocytic Leukaemia. Eur J Pharmacol. 2008 Sep 4;591(1-3):102-5. [3]. Ikezoe T, et al. A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies. Leukemia. 2009 Sep;23(9):1564-76.

GW843682X Dilution Calculator

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GW843682X Molarity Calculator

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Preparing Stock Solutions of GW843682X

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0944 mL 10.4721 mL 20.9442 mL 41.8883 mL 52.3604 mL
5 mM 0.4189 mL 2.0944 mL 4.1888 mL 8.3777 mL 10.4721 mL
10 mM 0.2094 mL 1.0472 mL 2.0944 mL 4.1888 mL 5.236 mL
50 mM 0.0419 mL 0.2094 mL 0.4189 mL 0.8378 mL 1.0472 mL
100 mM 0.0209 mL 0.1047 mL 0.2094 mL 0.4189 mL 0.5236 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.

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Background on GW843682X

GW843682X is a selective inhibitor of polo-like kinase 1 (PLK1) and polo-like kinase 3 (PLK3) (IC50 values are 2.2 and 9.1 nM respectively). GW843682X displays > 100-fold selectivity over ~30 other kinases tested including cdk1 and cdk2. GW843682X inhibits proliferation of most tumor cells in vitro and is selective over normal diploid fibroblasts.

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References on GW843682X

The cytotoxic effect of GW843682X on nasopharyngeal carcinoma.[Pubmed:27198987]

Anticancer Agents Med Chem. 2016;16(12):1640-1645.

BACKGROUND: GW843682X is a publicly available anti-cancer compound by inhibiting Polo-like kinase. Previous studies revealed that GW843682X inhibited the proliferation of various tumor cell lines. In this study, the cytotoxic effect of GW843682X was investigated on cell proliferation, cell cycle and apoptosis of nasopharyngeal carcinoma 5-8F cells. METHODS: Cell morphological changes were observed by inverted microscopy. Cell proliferation was tested by CCK8 assay. Cell cycle arrest and apoptosis were tested by flow cytometry. The mechanism of apoptosis was investigated by RT-PCR to determine the mRNA expression of IAP-1, IAP-2, XIAP, and survivin. RESULTS: GW843682X resulted in remarkable cell morphological changes with the increase of drug concentrations. CCK8 assay revealed that GW843682X inhibited the proliferation and induced apoptosis of 5-8F cells in a dose-dependent manner (IC50=62.5-125nmol/L). After treating 5-8F cells with different doses of GW843682X for 12 h, G2/M phase cells significantly increased while G0/G1 phase cells remarkably decreased. Interestingly, GW843682X signi fi cantly inhibited the mRNA expression of IAP-1 and survivin, which function as key regulators of mitosis and programmed cell death, and is overexpressed in many tumor types. The mechanism of cytotoxic effect is partially due to the inhibition of IAP gene expression. CONCLUSION: These findings indicated that GW843682X exhibited remarkable cytotoxic effects on nasopharyngeal carcinoma 5-8F cells by down-regulating IAP gene expression, suggesting that GW843682X may become a novel therapeutic agent for nasopharyngeal carcinoma.

An in-vitro evaluation of the polo-like kinase inhibitor GW843682X against paediatric malignancies.[Pubmed:21637161]

Anticancer Drugs. 2011 Jul;22(6):531-42.

Polo-like kinase 1 (PLK1) is a regulator of mitosis and its upregulation in tumours is often associated with poor prognosis. Although PLK1 inhibitors have already entered phase 1 clinical trials, little is known about their impact on the treatment of paediatric malignancies. Thus, we evaluated the concept of PKL1 inhibition by testing the effects of the PLK1 inhibitor GW843682X alone and in combination with the topoisomerase 1 inhibitor, camptothecin, against a panel of 18 paediatric tumour cell lines. Cytotoxicity was evaluated by MTT test and by caspase 3/7 activation. Expression of target was confirmed by western blot analysis. Expression of ATP binding cassette transporters was analysed by quantitative real-time reverse transcription PCR. GW843682X significantly inhibited cell growth in all 18 cell lines. Concentrations, which inhibited cell growth by 50% compared with untreated controls after 72 h, ranged from 0.02 to 11.7 mumol/l. Apart from the N-Myc-amplified neuroblastoma cell lines, the osteosarcoma cell lines MNNG-HOS and OST, which are highly resistant to standard anticancer drugs, were sensitive to GW843682X. The toxicity of GW843682X was dependent neither on the ATP binding cassette drug transporter expression nor on the p53 mutation status. Neither synergistic nor antagonistic effects were observed for the combination of GW843682X and camptothecin in 14 cell lines. GW843682X showed considerable toxicity against a panel of paediatric tumour cell lines suggesting that PLK1 inhibitors under clinical development should be evaluated against paediatric malignancies too.

In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1.[Pubmed:17267659]

Mol Cancer Ther. 2007 Feb;6(2):450-9.

Polo-like kinase 1 (PLK1) plays key roles in the regulation of mitotic progression, including mitotic entry, spindle formation, chromosome segregation, and cytokinesis. PLK1 expression and activity are strongly linked to proliferating cells. Many studies have shown that PLK1 expression is elevated in a variety of tumors, and high expression often correlates with poor prognosis. Using a variety of methods, including small-molecule inhibition of PLK1 function and/or activity, apoptosis in cancer cell lines, cell cycle arrest in normal cell lines, and antitumor activity in vivo have been observed. In the present study, we have examined the in vitro biological activity of a novel and selective thiophene benzimidazole ATP-competitive inhibitor of PLK1 and PLK3 (5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thioph ene-2-carboxamide, called compound 1). Compound 1 has low nanomolar activity against the PLK1 and PLK3 enzymes and potently inhibits the proliferation of a wide variety of tumor cell lines. In the lung adenocarcinoma cell line NCI-H460, compound 1 induces a transient G(2)-M arrest, mitotic spindle defects, and a multinucleate phenotype resulting in apoptosis, whereas normal human diploid fibroblasts arrest in G(2)-M and show little apoptosis. We also describe a cellular mechanistic assay that was developed to identify potent intracellular inhibitors of PLK1. In addition to its potential as a therapeutic agent for treating cancer, compound 1 is also a useful tool molecule for further investigation of the biological functions of PLK1 and PLK3.

Description

GW843682X is a selective, ATP-competitive inhibitor of PLK1 and PLK3, with IC50s of 2.2 nM and 9.1 nM, respectively, and is also >100-fold selective against ∼30 other kinases.

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