GSK461364

Alias: GSK461364; GSK 461364; GSK-461364; GSK461364A; GSK 461364A; GSK-461364A
Cat No.:V1576 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.
GSK461364 Chemical Structure CAS No.: 929095-18-1
Product category: PLK
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

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.

Biological Activity I Assay Protocols (From Reference)
Targets
PLK1 (Ki = 2.2 nM)
ln Vitro

GSK461364 has at least 390-fold higher selectivity for Plk1 than for Plk2 and Plk3, and 1,000-fold higher selectivity for a panel of 48 other kinases. It is a strong, selective, and reversible ATP-competitive Plk1 inhibitor (Ki, 2.2 nM)[1]. In A549 and PL45 cells, GSK461364 (GSK461364A, 250 nM) inhibiting plk1 results in a prolonged mitotic delay, aberrant mitotic exit, and p53 activation. When compared to cells with nonsilencing control siRNA, knockdown of p53 dramatically increases the sensitivity of the cells to GSK461364A (30 or 300 nM) in preventing outgrowth in A549 and NCI-H460 cells[2]. With a GI50 of less than 100 nM, GSK461364 can suppress the proliferation of 89% of cancer cell lines (66 out of 74 lines) and inhibit the growth of most proliferating cancer cell lines. In the G2-M phase of the A549 lung carcinoma line, GSK461364 (GSK461364A, >20 nM) inhibits cells while reducing those in the G1 phase. Caspases 1-3 and caspase-7 are activated in M-phase in cancer cells when GSK461364, which ranges from 10 to 250 nM, blocks cells in the G2 and M phases of the cell cycle[3]. Reduces the levels of PLK1 and pCDC25C, and causes a time- and dose-dependent rise in pHisH3, an OS cell line mitotic arrest marker, when added to the solution[4].

ln Vivo
In multiple xenograft tumor models, GSK461364 (50 mg/kg) administered intravenously (i.p.) once every two days for a total of twelve doses (q2d×12) displays varying degrees of tumor growth delay (TGD)[1].
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.
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.
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.
References

[1]. Phase I study of GSK461364, a specific and competitive Polo-like kinase 1 inhibitor, in patients with advanced solid malignancies. Clin Cancer Res. 2011 May 15;17(10):3420-30.

[2]. Sensitivity of cancer cells to Plk1 inhibitor GSK461364A is associated with loss of p53 function and chromosome instability. Mol Cancer Ther. 2010 Jul;9(7):2079-89.

[3]. Distinct concentration-dependent effects of the polo-like kinase 1-specific inhibitor GSK461364A, including differential effect on apoptosis. Cancer Res. 2009 Sep 1;69(17):6969-77.

[4]. Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel. Int J Oncol. 2016 Mar;48(3):1187-94.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C27H28F3N5O2S
Molecular Weight
543.6
Exact Mass
543.19
Elemental Analysis
C, 59.66; H, 5.19; F, 10.48; N, 12.88; O, 5.89; S, 5.90
CAS #
929095-18-1
Appearance
white solid powder
SMILES
C[C@H](C1=CC=CC=C1C(F)(F)F)OC2=C(SC(=C2)N3C=NC4=C3C=C(C=C4)CN5CCN(CC5)C)C(=O)N
InChi Key
ZHJGWYRLJUCMRT-QGZVFWFLSA-N
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
Chemical Name
5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide
Synonyms
GSK461364; GSK 461364; GSK-461364; GSK461364A; GSK 461364A; GSK-461364A
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~10 mg/mL (~18.4 mM)
Water: <1 mg/mL
Ethanol: ~30 mg/mL (~55.2 mM)
Solubility (In Vivo)
1%DMSO+30% polyethylene glycol+1%Tween 80: 30 mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
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.

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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.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00536835 Completed Drug: GSK461364 Lymphoma, Non-Hodgkin GlaxoSmithKline August 16, 2007 Phase 1
Biological Data
  • GSK461364


    Plk1 inhibitor GSK461364A causes aberrant mitotic arrest and micronucleation.

    GSK461364	GSK461364A activity in xenograft tumor models favors frequent lower dosing.

  • GSK461364

    Activity of Plk1 inhibitor on cancer cell lines from different tissue of origin.

    GSK461364

    Immunohistochemical staining of GSK461364A-treated tumor xenografts.2009 Sep 1;69(17):6969-77.

  • GSK461364

    Concentration and time-dependent growth inhibition and caspase-3/caspase-7 activation by GSK461364A.2009 Sep 1;69(17):6969-77.

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