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Purity: ≥98%
GSK-461364 (GSK461364; GSK 461364) is a novel, potent, selective, reversible and ATP-competitive small molecule Polo-like kinase 1 (PLK1) inhibitor with potential antitumor activity. It has a 2.2 nM Ki value and inhibits PLK1. There may be antineoplastic activity to GSK-461364. It exhibits a selectivity of over 1000 times against Plk2/3. GSK461364 selectively inhibits Plk1, causing reversible cell arrest at the G1 and G2 stage without apoptosis in normal cells and selective G2/M arrest followed by apoptosis in a variety of tumor cells. The non-ATP-competitive regulation of mitotic spindle function is carried out by the serine/threonine protein kinase Plk1.
| Targets |
PLK1 (Ki = 2.2 nM)
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
Kinase reactions are carried out using the Z'-Lyte Assay kit (Ser/Thr peptide 16) in a final assay volume of 10 μL. 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 1 mM DTT, 0.01% Brij 35, 0.01 mg/mL casein, 200 μM ATP, 200 μM Polo Box peptide (NH2-MAGPMQS[pT]PLNGAKK-OH), and 6 nM recombinant Plk1 (H6-tev-PLK 1-603) were briefly included in the reactions. For sixty minutes, Plk1 is preincubated with or without 0–1,000 nM GSK461364. Next, a 2 μM peptide is added to start reactions. Reactions are quenched, processed in accordance with the Z'-Lyte protocol, and read on a plate reader after 15 minutes at 23°C. Substratum and product standards are used to convert raw fluorescence values to product concentration. GraFit software is used to perform a two-parameter fit (IC50 and Hill coefficient) in order to determine IC50 values. An upper limit for the Ki*app of GSK461364 is found by applying the Cheng-Prusoff relationship for a competitive inhibitor (ATP Km*app=16 μM) to the IC50 value obtained with 60 minutes of preincubation of GSK461364, as the potency of inhibition for GSK461364 is observed to vary as a function of the ATP concentration in a manner consistent with an ATP-competitive mode of inhibition.
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| Cell Assay |
Cell lines are cultured in the suggested media in a humidified incubator at 37°C and 5% CO2. In triplicate, 1,000 cells are plated in each well of 96-well microtiter plates using culture media. The following day, one plate is harvested with 50 μL of CellTiter-Glo for a time 0 (T=0) measurement, and GSK461364 (GSK461364A) dissolved in DMSO or negative control (0.1% DMSO) is added.
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| Animal Protocol |
Nude mice are used to implant cells, which develop into tumor xenografts. Dosing started at around 100 mm3 for tumors. Every two days (q2d×6, q2d×12) or every four days (q4d×3), mice are given GSK461364 (GSK461364A) or the vehicle [4% DMA/Cremaphore (50:50), pH 5.6] intraperitoneally (i.p.) at nominal dose levels of 25, 50, and 100 mg/kg/dose. For n = 7–8 mice, the results are presented as the median tumor volume. For comparison, paclitaxel (30 mg/kg i.v.; q4d×3) is utilized as a positive control. Vernier calipers are used to measure tumors three times a week. The volume of the tumor is estimated from two-dimensional measurements using the following formula: tumor volume mm3 = (length × width2) × 0.5. The highest dose (approximately 4 g) that results in >20% mortality or >20% weight loss is known as the maximum tolerated dose. Tumor growth delay (TGD), partial regression (PR), or complete regression (CR) are three ways to characterize antitumor activity. The time difference (TGD) between the treated and control tumors to reach a predefined tumor volume (1,000 mm3) is represented. A PR is defined as a tumor's volume decreasing to half of its initial starting volume over a minimum of one week (based on three measurements in a row). A tumor's volume must decrease to less than 13 mm3 for at least one week in order to be considered CR.
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| References |
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| Additional Infomation |
5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide is a member of (trifluoromethyl)benzenes.
Polo-like Kinase 1 Inhibitor GSK461364 is a small molecule Polo-like kinase 1 (PLK1) inhibitor with potential antineoplastic activity. Polo-like kinase 1 inhibitor GSK461364 selectively inhibits Plk1, inducing selective G2/M arrest followed by apoptosis in a variety of tumor cells while causing reversible cell arrest at the G1 and G2 stage without apoptosis in normal cells. Plk1, named after the polo gene of Drosophila melanogaster, is a serine/threonine protein kinase involved in regulating mitotic spindle function in a non-ATP competitive manner. |
| Molecular Formula |
C27H28F3N5O2S
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| Molecular Weight |
543.6
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| Exact Mass |
543.191
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| Elemental Analysis |
C, 59.66; H, 5.19; F, 10.48; N, 12.88; O, 5.89; S, 5.90
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| CAS # |
929095-18-1
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| Related CAS # |
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| PubChem CID |
15983966
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| Appearance |
white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
658.0±65.0 °C at 760 mmHg
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| Flash Point |
351.7±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.645
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| LogP |
3.34
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
38
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| Complexity |
814
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C(N1CCN(C)CC1)C1C=CC2=C(N(C3SC(C(=O)N)=C(O[C@@H](C4C=CC=CC=4C(F)(F)F)C)C=3)C=N2)C=1
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| InChi Key |
ZHJGWYRLJUCMRT-QGZVFWFLSA-N
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| InChi Code |
InChI=1S/C27H28F3N5O2S/c1-17(19-5-3-4-6-20(19)27(28,29)30)37-23-14-24(38-25(23)26(31)36)35-16-32-21-8-7-18(13-22(21)35)15-34-11-9-33(2)10-12-34/h3-8,13-14,16-17H,9-12,15H2,1-2H3,(H2,31,36)/t17-/m1/s1
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| Chemical Name |
5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.60 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.60 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.60 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8396 mL | 9.1979 mL | 18.3959 mL | |
| 5 mM | 0.3679 mL | 1.8396 mL | 3.6792 mL | |
| 10 mM | 0.1840 mL | 0.9198 mL | 1.8396 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00536835 | Completed | Drug: GSK461364 | Lymphoma, Non-Hodgkin | GlaxoSmithKline | August 16, 2007 | Phase 1 |
 Plk1 inhibitor GSK461364A causes aberrant mitotic arrest and micronucleation.
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Activity of Plk1 inhibitor on cancer cell lines from different tissue of origin.
Immunohistochemical staining of GSK461364A-treated tumor xenografts.Cancer Res.2009 Sep 1;69(17):6969-77. |
Concentration and time-dependent growth inhibition and caspase-3/caspase-7 activation by GSK461364A.Cancer Res.2009 Sep 1;69(17):6969-77. |
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COA
GSK461364A activity in xenograft tumor models favors frequent lower dosing.
