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GSK461364 PLK inhibitor

Cat.No.S2193

GSK461364 (GSK461364A) inhibits purified Plk1 with Ki of 2.2 nM in a cell-free assay. It is more than 1000-fold selective against Plk2/3.
GSK461364 PLK inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 543.6

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Quality Control

Batch: Purity: 99.97%
99.97

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human MV4-11 cells Cytotoxicity assay 24 h Cytotoxicity against human MV4-11 cells after 24 hrs by CellTiter-Blue assay, GI50=0.679 μM 26191363
HEK293T Antiproliferative assay 72 hrs Antiproliferative activity against HEK293T cells measured after 72 hrs by CellTiter-Blue assay, IC50=0.001μM 28792760
MDA-MB-231 Antiproliferative assay 72 hrs Antiproliferative activity against human MDA-MB-231 cells measured after 72 hrs by CellTiter-Blue assay, IC50=0.001μM 28792760
MM1S Antiproliferative assay 72 hrs Antiproliferative activity against human MM1S cells measured after 72 hrs by CellTiter-Blue assay, IC50=0.001μM 28792760
MDA-MB-23 Function assay 6 hrs Inhibition of PLK1 in human MDA-MB-23 cells assessed as decrease in TCTP phosphorylation after 6 hrs by Western blot method, IC50<0.1μM 28792760
HEK293T Function assay 6 hrs Inhibition of PLK1 in HEK293T cells assessed as decrease in TCTP phosphorylation after 6 hrs by Western blot method, IC50<0.1μM 28792760
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells 29435139
SJ-GBM2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells 29435139
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells 29435139
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells 29435139
BT-37 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells 29435139
NB-EBc1 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells 29435139
U-2 OS qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells 29435139
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
LAN-5 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells 29435139
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells 29435139
Rh18 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells 29435139
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB1643 cells 29435139
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells) 29435139
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-MC cells 29435139
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-12 cells 29435139
LAN-5 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for LAN-5 cells 29435139
NB-EBc1 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB-EBc1 cells 29435139
SJ-GBM2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SJ-GBM2 cells 29435139
BT-37 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-37 cells 29435139
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for TC32 cells 29435139
MG 63 (6-TG R) qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for MG 63 (6-TG R) cells 29435139
fibroblast cells qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for control Hh wild type fibroblast cells 29435139
Rh41 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells 29435139
Rh18 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh18 cells 29435139
Rh30 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh30 cells 29435139
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for OHS-50 cells 29435139
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-SH cells 29435139
Click to View More Cell Line Experimental Data

Solubility

In vitro
Batch:

Ethanol : 30 mg/mL

DMSO : 10 mg/mL (18.39 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

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Mass Concentration Volume Molecular Weight
Dilution Calculator Molecular Weight Calculator

In vivo
Batch:

In vivo Formulation Calculator (Clear solution)

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%
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% ddH2O
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Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Chemical Information, Storage & Stability

Molecular Weight 543.6 Formula

C27H28F3N5O2S

 Storage (From the date of receipt)
CAS No. 929095-18-1 Download SDF Storage of Stock Solutions

Synonyms GSK461364A 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

Mechanism of Action

Features
Demonstrates >390-fold selectivity for Plk1 relative to Plk2 and Plk3.
Targets/IC50/Ki
PLK1
(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. RNA silencing of WT p53 increases the antiproliferative activity of this compound. As many cancer therapies tend to be more effective in p53 WT patients, the higher sensitivity of p53-deficient tumors toward this chemical could potentially offer an opportunity to treat tumors that are refractory to other chemotherapies as well as early line therapy for these genotypes. This compound 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. It 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 concentrations of this agent and arrest at M phase at lower concentrations. Currently, it is in a dose-escalation first-time-in-human trial. Cell lines with mutations in the TP53 gene tended to be more sensitive to this compound, 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. In preclinical testing, this chemical 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.

Kinase Assay
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 this compound 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 this chemical is determined.
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. This compound shows clear antitumor activity in human tumor xenograft models. It shows a dose-dependent mitotic arrest in mouse xenografts, which correlates with effects on tumor growth. Intraperitoneal administration of this chemical causes regression or tumor growth delay in different xenograft models, including Colo205 xenografts. Suppression of Plk1 in vivo by using this agent results in mitotic arrest with aberrant mitotic figures consisting of monopolar or collapsed mitotic spindles.

References

Applications

Methods Biomarkers Images PMID
Western blot p-Myt1 / Myt1 / Plk1
S2193-WB1
26597303

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00536835 Completed
Lymphoma Non-Hodgkin
GlaxoSmithKline
 August 16 2007 Phase 1

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Handling Instructions

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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 of it.

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

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