GSK-923295

CENP-E inhibitor,small-molecule CAS# 1088965-37-0

GSK-923295

Catalog No. BCC1608----Order now to get a substantial discount!

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Chemical structure

GSK-923295

3D structure

Chemical Properties of GSK-923295

Cas No. 1088965-37-0 SDF Download SDF
PubChem ID 46898058 Appearance Powder
Formula C32H38ClN5O4 M.Wt 592.14
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 30 mg/mL (50.66 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 3-chloro-N-[(2S)-1-[[2-(dimethylamino)acetyl]amino]-3-[4-[8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl]phenyl]propan-2-yl]-4-propan-2-yloxybenzamide
SMILES CC(C)OC1=C(C=C(C=C1)C(=O)NC(CC2=CC=C(C=C2)C3=CN4C=CC=C(C4=N3)C(C)O)CNC(=O)CN(C)C)Cl
Standard InChIKey WHMXDBPHBVLYRC-OFVILXPXSA-N
Standard InChI InChI=1S/C32H38ClN5O4/c1-20(2)42-29-13-12-24(16-27(29)33)32(41)35-25(17-34-30(40)19-37(4)5)15-22-8-10-23(11-9-22)28-18-38-14-6-7-26(21(3)39)31(38)36-28/h6-14,16,18,20-21,25,39H,15,17,19H2,1-5H3,(H,34,40)(H,35,41)/t21-,25-/m0/s1
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 GSK-923295

DescriptionGSK-923295 is a small-molecule inhibitor of the mitotic kinesin centromere-associated protein E (CENP-E) with Ki value of 3.2 nM.
TargetsCENP-E    
IC503.2 nM (Ki)     

Protocol

Cell Assay [1]
Cell-growth inhibition assays are performed by MDS in 384-well plates, and DNA content of fixed cells stained with DAPI using an Incell 1000 (GE) is analyzed. DNA content is determined 24 h after seeding (T0) and after exposure to varying concentrations of GSK-923295 (0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, and 100 μM) for an additional 72 h (T72). All T72 measurements are normalized to T0. Curves are analyzed using the XLfit curve-fitting tool to determine the concentration of GSK923295 yielding 50% growth inhibition relative to T0 and Ymax values (GI50)[1].

Animal Administration [3]
Mice[3] CB17 scid mice are used to propagate subcutaneously implanted neuroblastoma tumors. Tumor diameters are measured using calipers. Tumor volumes are calculated. Once tumor volume exceeds 200 mm3, mice are randomized (n=10 per arm) to receive either GSK923295 125 mg/kg IP or vehicle (96% acidified water, 2% DMAC, 2% CREM) for a total of 6 doses using a 3 days on, 4 days off, 3 days on regimen.

References:
[1]. Wood KW, et al. Antitumor activity of an allosteric inhibitor of centromere-associated protein-E. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5839-44. [2]. Mayes PA, et al. Mitogen-activated protein kinase (MEK/ERK) inhibition sensitizes cancer cells to centromere-associated protein E (CENP-E) inhibition. Int J Cancer. 2013 Feb 1;132(3):E149-57. [3]. Balamuth NJ, et al. Serial transcriptome analysis and cross-species integration identifies centromere-associated protein E as a novel neuroblastoma target. Cancer Res. 2010 Apr 1;70(7):2749-58.

GSK-923295 Dilution Calculator

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GSK-923295 Molarity Calculator

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Preparing Stock Solutions of GSK-923295

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.6888 mL 8.4439 mL 16.8879 mL 33.7758 mL 42.2197 mL
5 mM 0.3378 mL 1.6888 mL 3.3776 mL 6.7552 mL 8.4439 mL
10 mM 0.1689 mL 0.8444 mL 1.6888 mL 3.3776 mL 4.222 mL
50 mM 0.0338 mL 0.1689 mL 0.3378 mL 0.6755 mL 0.8444 mL
100 mM 0.0169 mL 0.0844 mL 0.1689 mL 0.3378 mL 0.4222 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 GSK-923295

GSK923295 is a specific inhibitor of CENP-E kinesin motor with IC50 value of 3.2 nM [1].

Centromere-associated protein E (CENP-E) is a mitotic kinesin, which is the connect of mitosis process with the mitotic checkpoint signaling. It Interacts with spindle microtubules and contribute to the chromosome alignment, and thus it regulates the cell-cycle transition from metaphase to anaphase.

When asynchronous cultured cells were exposed to GSK923295, the penetrant cell-cycle delay in mitosis was observed, which accompanied with morphological changes similar to RNAi-mediated knockdown of CENP-E mRNA. It indicated a significant inhibition of CENP-E by GSK923295. In the presence of GSK9232195, CENP-E microtubule (MT)-stimulated ATPase showed a dramatic slowing of release of ADP and Pi, where the ATP-bound form was stabilized and the activity of CENP-E was inhibited. This observation suggested GSK923295 inhibited CENP-E via the suppression of MT-stimulated ATPase [1].

In mouse model, mice bearing xenografts of the Colo205 colon tumor cell line were administered with GSK923295 of 125 mg/kg. The result showed GSK923295-induced cell-cycle changes of tumor cells and increased scattered apoptosis body. Additionally, long-term study via measuring tumor volume revealed significant antitumor activity of GSK923295, in a manner of dose-dependent [1].

Reference:
[1] Wood K W et al. , Antitumor activity of an allosteric inhibitor of centromere-associated protein-E. 2010, 107 (13): 5839-5844.

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References on GSK-923295

Small Molecules Identified from a Quantitative Drug Combinational Screen Resensitize Cisplatin's Response in Drug-Resistant Ovarian Cancer Cells.[Pubmed:29982103]

Transl Oncol. 2018 Aug;11(4):1053-1064.

Drug resistance to chemotherapy occurs in many ovarian cancer patients resulting in failure of treatment. Exploration of drug resistance mechanisms and identification of new therapeutics that overcome the drug resistance can improve patient prognosis. Following a quantitative combination screen of 6060 approved drugs and bioactive compounds in a cisplatin-resistant A2780-cis ovarian cancer cell line, 38 active compounds with IC50s under 1 muM suppressed the growth of cisplatin-resistant ovarian cancer cells. Among these confirmed compounds, CUDC-101, OSU-03012, oligomycin A, VE-821, or Torin2 in a combination with cisplatin restored cisplatin's apoptotic response in the A2780-cis cells, while SR-3306, GSK-923295, SNX-5422, AT-13387, and PF-05212384 directly suppressed the growth of A2780-cis cells. One of the mechanisms for overcoming cisplatin resistance in these cells is mediated by the inhibition of epidermal growth factor receptor (EGFR), though not all the EGFR inhibitors are equally active. The increased levels of total EGFR and phosphorylated-EGFR (p-EGFR) in the A2780-cis cells were reduced after the combined treatment of cisplatin with EGFR inhibitors. In addition, a knockdown of EGFR mRNA reduced cisplatin resistance in the A2780-cis cells. Therefore, the top active compounds identified in this work can be studied further as potential treatments for cisplatin-resistant ovarian cancer. The quantitative combinational screening approach is a useful method for identifying effective compounds and drug combinations against drug-resistant cancer cells.

Description

GSK-923295 is a special, allosteric inhibitor of centromere-associated protein-E (CENP-E) kinesin motor ATPase activity, with Ki of 3.2±0.2 nM and 1.6± 0.1 nM for human and canine, respectively.

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