GSK461364

For research use only.

Catalog No.S2193

19 publications

GSK461364 Chemical Structure

CAS No. 929095-18-1

GSK461364 inhibits purified Plk1 with Ki of 2.2 nM in a cell-free assay. It is more than 1000-fold selective against Plk2/3. Phase 1.

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Selleck's GSK461364 has been cited by 19 publications

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Biological Activity

Description GSK461364 inhibits purified Plk1 with Ki of 2.2 nM in a cell-free assay. It is more than 1000-fold selective against Plk2/3. Phase 1.
Features Demonstrates >390-fold selectivity for Plk1 relative to Plk2 and Plk3.
Targets
PLK1 [1]
(Cell-free assay)
2.2 nM(Ki)
In vitro

GSK461364 inhibits cancer cell line proliferation from multiple origins with minimal toxicity in nondividing human cells. [1] RNA silencing of WT p53 increases the antiproliferative activity of GSK461364. As many cancer therapies tend to be more effective in p53 WT patients, the higher sensitivity of p53-deficient tumors toward GSK461364 could potentially offer an opportunity to treat tumors that are refractory to other chemotherapies as well as early line therapy for these genotypes. GSK461364 is a thiophene amide that inhibits purified Plk1 enzyme in vitro with a Ki of 2 nM and has >100-fold selectivity for Plk1 compared with Plk2 and Plk3. GSK461364 is a potent inhibitor of cell proliferation causing 50% growth inhibition (GI50) below 100 nM in most of the cell lines tested with limited toxicity against human nonproliferating cells. Inhibition of cell cycle progression is concentration dependent with initial delay at G2 phase at high GSK461364 concentrations and arrest at M phase at lower concentrations. Currently, GSK461364 is in a dose-escalation first-time-in-human trial. Cell lines with mutations in the TP53 gene tended to be more sensitive to GSK461364, and that inhibiting the p53 response by RNA silencing confers increased sensitivity in some p53 wild-type (WT) cells. Furthermore, these more sensitive cell lines also have increased levels of chromosome instability, a characteristic associated with TP53 mutations. [2] In preclinical testing, GSK461364 shows antiproliferative activity against multiple (>120) tumor cell lines and potently inhibits the proliferation of greater than 83% and 91% of these cell lines, with IC50 values lower than 50 and 100 nM, respectively. [3]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human MV4-11 cells MmDFR5l1d3SxeHnjbZR6KGG|c3H5 MYSyOEBp NYm0TZJCS3m2b4TvfIlkcXS7IHHnZYlve3RiaIXtZY4hVVZ2LUGxJINmdGy|IHHmeIVzKDJ2IHjyd{BjgSCFZXzsWIl1\XJvQnz1[UBie3OjeTygS2k2OD1yLk[3PUDPxE1? NXLab4VtOjZzOUGzOlM>

... Click to View More Cell Line Experimental Data
Assay
Methods Test Index PMID
Western blot
p-Myt1 / Myt1 / Plk1 ; 

PubMed: 26597303     


NSCLC cell lines were incubated with dimethyl sulfoxide (vehicle control), BI2536, volasertib, or GSK461364 at the indicated concentrations for 2 hours. Cells were then lysed and subjected to Western blotting with the indicated primary antibodies.

26597303
In vivo Cell culture growth inhibition by GSK461364 can be cytostatic or cytotoxic but leads to tumor regression in xenograft tumor models under proper dose scheduling. GSK461364 shows clear antitumor activity in human tumor xenograft models. [1] GSK461364 shows a dose-dependent mitotic arrest in mouse xenografts, which correlates with effects on tumor growth. [2] Intraperitoneal administration of GSK461364 causes regression or tumor growth delay in different xenograft models, including Colo205 xenografts. Suppression of Plk1 in vivo by using GSK461364 results in mitotic arrest with aberrant mitotic figures consisting of monopolar or collapsed mitotic spindles. [3]

Protocol

Kinase Assay:[1]
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Enzyme assays:

Kinase reactions are performed in a final assay volume of 10 μL using the Z-Lyte Assay kit (Ser/Thr peptide 16). Briefly, reactions contains 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 minutes with 0 to 1 μM GSK461364. Reactions are then initiated by the addition of 2 μM peptide. After 15 minutes at 23 °C, reactions are quenched and processed according the Z′-Lyte protocol and read on an EnVision plate reader. Raw fluorescence values are converted to concentration of product formed using substrate and product standards. 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 for GSK461364 is determined.
Cell Research:[2]
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  • Cell lines: Prostate(LNCap,PC3), Cervix(HeLa), Pancreas(ASPC1), Sarcoma(Saos-2)Ovary(OVCAR8), Stomach(NCI-N87), Melanoma(SKMEL3,A431, MALME3M), Colon(Colo205,SW620,HCT116), Breast(SKBR3,MDA-MB-453,MCF7), Lung(NCI-H82,MV522,NCI-H522), etc.
  • Concentrations: 10 nM
  • Incubation Time: 72 hours
  • Method: Cancer cell lines are seeded into 384-well microtiter plates. After seeding, the cells are incubated at 37 °C in 5% CO2 for 24 hours. GSK461364 is added to each cell line at 10 nM with a nontreated control. A zero-time (T = 0) value is read for each cell line. After 72 hours, the medium containing GSK461364 or DMSO control is aspirated from all of the remaining cells and the cell nuclei are stained with 4′,6-diamidino-2-phenylindole and the fluorescent intensity measured using an InCell1000 High Content Analyzer. The percent intensity of the 4′,6-diamidino-2-phenylindole stain at 72 hours, relative to intensity at time zero, is calculated for each concentration of GSK461364 in each of the triplicate wells.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Nude mice bearing Colo205 (colorectal) xenograft tumors
  • Dosages: 25, 50, and 100 mg/kg
  • Administration: Administered via i.p.(every 2 days or every 4 days)
    (Only for Reference)

Solubility (25°C)

In vitro Ethanol 30 mg/mL (55.18 mM)
DMSO 10 mg/mL (18.39 mM)
Water Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
1% DMSO+30% polyethylene glycol+1% Tween 80
For best results, use promptly after mixing. 		30 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 543.6
Formula

C27H28F3N5O2S
CAS No. 929095-18-1
Storage powder
in solvent
Synonyms N/A
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

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Frequently Asked Questions

  • Question 1:

    I would like to know whether the recommended in vivo formulation will be suitable for i.p. injections

  • Answer:

    GSK461364 in 1% DMSO+30% polyethylene glycol+1% Tween 80 at 30mg/ml is a suspension, and it is fine for oral gavage.

selleck catalog

PLK Signaling Pathway Map

PLK Inhibitors with Unique Features

  • Pan Plk Inhibitors

    BI 2536 : Pan-Plk1, Plk1, IC50=0.83 nM; Plk2, IC50=3.5 nM; Plk3, IC50=9 nM.

  • Most Potent Plk Inhibitor

    BI 2536 : Plk1, IC50=0.83 nM.

  • Plk Inhibitor in Clinical Trial

    Volasertib (BI 6727) : Phase III for acute myeloid leukaemia.

  • Newest Plk Inhibitor

    Ro3280 New : Potent, highly selective inhibitor of Polo-like kinase 1 (PLK1) with IC50 of 3 nM.

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  • BI 2536

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    Features:The first potent and selective Plk1 inhibitor that induces all hallmarks of Plk1 inhibition.

  • Rigosertib (ON-01910)

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  • Volasertib (BI 6727)

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    Features:A high volume of distribution, indicating good tissue penetration, and a long terminal half-life.

  • MLN0905

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  • Ro3280

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID