GSK461364

Plk1 inhibitor CAS# 929095-18-1

GSK461364

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Quality Control of GSK461364

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Chemical structure

GSK461364

3D structure

Chemical Properties of GSK461364

Cas No. 929095-18-1 SDF Download SDF
PubChem ID 15983966 Appearance Powder
Formula C27H28F3N5O2S M.Wt 543.6
Type of Compound N/A Storage Desiccate at -20°C
Synonyms GSK461364A
Solubility DMSO : 50 mg/mL (91.98 mM; Need ultrasonic)
Chemical Name 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide
SMILES CC(C1=CC=CC=C1C(F)(F)F)OC2=C(SC(=C2)N3C=NC4=C3C=C(C=C4)CN5CCN(CC5)C)C(=O)N
Standard InChIKey ZHJGWYRLJUCMRT-QGZVFWFLSA-N
Standard InChI 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
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 GSK461364

DescriptionGSK461364 is a inhibitor of Plk1 with a Ki value of 2.2 nM.
TargetsPLK1    
IC502.2 nM(Ki)     

Protocol

Kinase Assay [3]
Kinase reactions are performed in a final assay volume of 10 μL using the Z'-Lyte Assay kit (Ser/Thr peptide 16). Briefly, reactions contained 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). Plk1 is preincubated for 60 min in the presence or absence of 0 to 1,000 nM GSK461364. Reactions are then initiated by the addition of 2 μM peptide. After 15 min at 23°C, reactions are quenched and processed according the Z'-Lyte protocol and read on an plate reader. Raw fluorescence values are converted to concentration of product formed using substrate and product standards. IC50 values are determined using a two-parameter fit (Hill coefficient and IC50) using GraFit software. Because 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, an upper limit for the Ki*app for GSK461364 is determined by applying the Cheng-Prusoff relationship for a competitive inhibitor (ATP Km*app=16 μM) to the IC50 value obtained with 60 min preincubation of GSK461364.

Cell Assay [3]
Cell lines grow in the recommended media at 37°C, 5% CO2 in a humidified incubator. Cells are plated in triplicate 96-well microtiter plates at 1,000 cells per well in culture media. GSK461364 (GSK461364A) dissolved in DMSO or negative control (0.1% DMSO) are added the following day, and one plate is harvested with 50 μL of CellTiter-Glo for a time 0 (T=0) measurement.

Animal Administration [3]
Cells are implanted in Nude mice and grown as tumor xenografts. Dosing began when tumors achieve appr 100 mm3. GSK461364 (GSK461364A) or the vehicle [4% DMA/Cremaphore (50:50), pH 5.6] is given i.p. to mice every 2 d (q2d×6, q2d×12) or every 4 d (q4d×3) at nominal dose levels of 25, 50, and 100 mg/kg/dose. Results are reported as median tumor volume for n=7 to 8 mice. Paclitaxel (30 mg/kg i.v.; q4d×3) is used as a positive control for comparison. Tumors are measured thrice a week with Vernier calipers, and tumor volume is calculated from two-dimensional measurements using an equation approximating the volume of a prolate ellipsoid [tumor volume mm3=(length × width2) × 0.5]. The maximum tolerated dose is defined as the highest dose that produces >20% mortality or >20% weight loss (appr 4 g). Antitumor activity is defined as tumor growth delay (TGD), partial regression (PR), or complete regression (CR). TGD represents the time differential between the treated and control tumors to reach a predetermined tumor volume of 1,000 mm3. PR is defined as a decrease in an individual tumor volume to one-half the initial starting volume for at least 1 wk (three consecutive measurements). CR is defined as a decrease in an individual tumor volume to <13 mm3 for at least 1 wk.

References:
[1]. Olmos D, et al. 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]. Degenhardt Y, et al. 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]. Gilmartin AG, et al. 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]. Chou YS, et al. 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.

GSK461364 Dilution Calculator

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GSK461364 Molarity Calculator

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Preparing Stock Solutions of GSK461364

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.8396 mL 9.1979 mL 18.3959 mL 36.7918 mL 45.9897 mL
5 mM 0.3679 mL 1.8396 mL 3.6792 mL 7.3584 mL 9.1979 mL
10 mM 0.184 mL 0.9198 mL 1.8396 mL 3.6792 mL 4.599 mL
50 mM 0.0368 mL 0.184 mL 0.3679 mL 0.7358 mL 0.9198 mL
100 mM 0.0184 mL 0.092 mL 0.184 mL 0.3679 mL 0.4599 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 GSK461364

GSK461364 is a potent and reversible ATP competitive Plk1 inhibitor. Polo-like kinases (Plk) are a family of serine threonine kinases that are critical regulators of DNA damage response and cell cycle progression.

In vitro: GSK461364 showed at least 390-fold greater selectivity for Plk1 than for Plk2 and Plk3 and 1,000-fold greater than for 48 other kinases. The drug showed antiproliferative activity against multiple (>120) tumor cell lines and potently inhibited the proliferation of greater than 83% and 91% of these cell lines [1].

In vivo: Intraperitoneal administration of GSK461364 caused regression or tumor growth delay in different xenograft models. In vivo suppression of Plk1 by using GSK461364 resulted in mitotic arrest with aberrant mitotic figures consisting of monopolar or collapsed mitotic spindles [1].

Clinical trial: The final recommended phase II dose for GSK461364 was 225 mg administered intravenously. Moreover, GSK461364 was suggested to involve coadministration of prophylactic anticoagulation for further clinical evaluation [1].

Reference:
[1] Olmos D, Barker D, Sharma R, Brunetto AT, Yap TA, Taegtmeyer AB, Barriuso J, Medani H, Degenhardt YY, Allred AJ, Smith DA, Murray SC, Lampkin TA, Dar MM, Wilson R, de Bono JS, Blagden SP.  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.

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References on GSK461364

Overexpression of human ABCB1 in cancer cells leads to reduced activity of GSK461364, a specific inhibitor of polo-like kinase 1.[Pubmed:25192198]

Mol Pharm. 2014 Oct 6;11(10):3727-36.

Polo-like kinase 1 (Plk1) is a serine/threonine kinase involved in the regulation of mitosis and is overexpressed in many tumor types. Inhibition of Plk1 leads to cell cycle arrest, onset of apoptosis, and cell death, thus Plk1 has emerged as an important target for cancer treatment. GSK461364 is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting G2/M cell cycle arrest at low concentrations. However, as is the case for many therapeutic drugs, the risk of developing drug resistance to GSK461364 can present a therapeutic challenge to clinicians. Since the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 is one of the most common mechanisms of drug resistance, we aimed to investigate the effect of ABCB1 on the cellular efficacy of GSK461364. In this study, we observed a significantly reduced activity of GSK461364 in cells overexpressing human ABCB1. We showed that GSK461364 stimulates the ABCB1 ATPase activity and competitively inhibits ABCB1-mediated efflux of calcein-AM in a concentration-dependent manner. Moreover, as a way to assess the impact of ABCB1 on the efficacy of GSK461364, we evaluated the G2/M cell cycle arrest and apoptosis induced by GSK461364. We discovered that, by inhibiting the function of ABCB1, the reduced G2/M cell cycle arrest, apoptosis, and sensitivity to GSK461364 treatment in ABCB1-overexpressing cells can be significantly restored. In conclusion, in order to achieve a better therapeutic outcome, combination therapy of GSK461364 with a modulator of ABCB1 should be further investigated as a potential treatment approach.

Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel.[Pubmed:26794530]

Int J Oncol. 2016 Mar;48(3):1187-94.

Polo-like kinase 1 (PLK1), a serine/threonine kinase and an oncogene, is crucial in regulating cell cycle progression. PLK1 also has been demonstrated as a potential target of osteosarcoma (OS) by using short hairpin RNA libraries in lentiviral vectors for screening of protein kinase. In preclinical studies, GSK461364, a potent and selective ATP-competitive PLK1 inhibitor, showed antiproliferative activity against multiple tumor cell lines. In the present study, we evaluated the expression level of PLK1 in OS and explored the cytotoxic mechanism of GSK461364 against OS. PLK1 was significantly overexpressed in OS compared with normal osteoblasts and other types of sarcoma. GSK461364 inhibited PLK1 and caused mitotic arrest by inducing G2/M arrest in OS cells. Moreover, GSK461364 exerted a cytotoxic effect by inducing apoptosis in OS, and induced cellular senescence in OS cell lines, as indicated by an increased senescence-associated beta-galactosidase activity and enhanced DcR2 and interleukin-1alpha expression. In addition, we demonstrated a synergistic cytotoxic effect of GSK461364 and paclitaxel, possibly resulting from combined mitotic arrest. In conclusion, the present study revealed that PLK1 was overexpressed in OS and that GSK461364 exerted its cytotoxic effect on OS by inducing mitotic arrest and subsequent apoptosis and induced cellular senescence; therefore, senescence-associated markers can be used as treatment biomarkers, and a combination of GSK461364 and paclitaxel can potentially treat OS.

The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models.[Pubmed:28036269]

Oncotarget. 2017 Jan 24;8(4):6730-6741.

Polo-like kinase 1 (PLK1) is a serine/threonine kinase that promotes G2/M-phase transition, is expressed in elevated levels in high-risk neuroblastomas and correlates with unfavorable patient outcome. Recently, we and others have presented PLK1 as a potential drug target for neuroblastoma, and reported that the BI2536 PLK1 inhibitor showed antitumoral actvity in preclinical neuroblastoma models. Here we analyzed the effects of GSK461364, a competitive inhibitor for ATP binding to PLK1, on typical tumorigenic properties of preclinical in vitro and in vivo neuroblastoma models. GSK461364 treatment of neuroblastoma cell lines reduced cell viability and proliferative capacity, caused cell cycle arrest and massively induced apoptosis. These phenotypic consequences were induced by treatment in the low-dose nanomolar range, and were independent of MYCN copy number status. GSK461364 treatment strongly delayed established xenograft tumor growth in nude mice, and significantly increased survival time in the treatment group. These preclinical findings indicate PLK1 inhibitors may be effective for patients with high-risk or relapsed neuroblastomas with upregulated PLK1 and might be considered for entry into early phase clinical trials in pediatric patients.

BI 6727 and GSK461364 suppress growth and radiosensitize osteosarcoma cells, but show limited cytotoxic effects when combined with conventional treatments.[Pubmed:25089571]

Anticancer Drugs. 2015 Jan;26(1):56-63.

Polo-like kinase 1 (PLK1), a key regulator of mitosis, is often overexpressed in childhood cancers and is associated with poor prognosis. Previous reports have shown that inhibition of PLK1 might serve as a promising anticancer treatment for osteosarcoma. In this study, we tested the second-generation PLK1 inhibitors BI 6727 and GSK461364 in HOS and MG-63 cell lines, both as a single agent and in combination with methotrexate, cisplatin, vinblastine, doxorubicin, or ionizing radiation. Both PLK1 inhibitors worked equally in terms of cell growth arrest, apoptosis induction, and radiosensitization. Combining BI 6727 or GSK461364 with conventional treatments, however, showed trivial synergistic antitumor effects in vitro. Our results reinforce the potential use of PLK1 inhibitors for a pharmacologic intervention in osteosarcoma, although their applicability in polychemotherapeutic regimens deserves further investigation.

Description

GSK461364 is a selective, reversible and ATP-competitive Polo-like kinase 1 (PLK1) inhibitor with a Ki value of 2.2 nM.

Keywords:

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