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GSK1120212

Cat. No. M1759
GSK1120212 Structure
Synonym:

JTP-74057, GSK212

Size Price Availability Quantity
10mg USD 80 In stock
50mg USD 120 In stock
100mg USD 150 In stock
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Quality Control
Biological Activity

GSK1120212 (JTP-74057) is a potent and selective allosteric inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes with promising antitumor activity in a phase I clinical trial (ASCO 2010). GSK1120212 (JTP-74057) inhibits MEK1/2 kinase activity and prevents Raf-dependent MEK phosphorylation (S217 for MEK1), producing prolonged p-ERK1/2 inhibition. Potent cell growth inhibition was evident in most tumor lines with mutant BRAF or Ras. In xenografted tumor models, GSK1120212 orally dosed once daily had a long circulating half-life and sustained suppression of p-ERK1/2 for more than 24 hours; GSK1120212 also reduced tumor Ki67, increased p27 (Kip1/CDKN1B), and caused tumor growth inhibition in multiple tumor models.

Protocol
Cell Experiment
Cell lines DO4, MM415, MM485, SK-MEL-2, MaMel30I and MaMel27II
Preparation method cells were plated in 96-well plates with a density of 4000-8000 cells per well and incubated for 24 h at 37 °C with 5% C02. Then cells were incubated with increasing drug concentrations and their combinations. Cell viability was measured with the CellTiter-Glo (CTG) Luminescent Cell Viability Assay (Promega; Madison, Wisconsin, USA) according to the manufacturer’s protocol. Luminescence was measured on the SynergyHT plate reader (BioTek, Vermont, USA) using Gen5 software (Version 1.11.5). For apoptotic assays, cells were plated in 12-well plates and treated with DMSO, trametinib, metformin or combinations. After 72hrs apoptosis was assessed using the Dead Cell Apoptosis Kit with Annexin V Alexa Fluor 488 & Propidium Iodide according to the manufacturer’s protocol (Invitrogen; V13241) with the AccuriC6 Flow Cytometer using the CFlow software (Version 1.0.227.4).
Concentrations 0.2-30nM
Incubation time 72 h
Animal Experiment
Animal models Tumor induction on the skin of the Tyr::CreERT2; PtenLoxP/LoxP;BrafCA/+ mice
Formulation dissolved in 0.5% hydroxypropyl methylcellulose (Sigma-Aldrich) and 0.2% Tween-80 (Sigma-Aldrich)
Dosages 0.75 mg/kg, once daily
Administration orally
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 615.39
Formula C26H23FIN5O4
CAS Number 871700-17-3
Purity 100.00%
Solubility DMSO
Storage at -20°C
Customer Product Validations & Biological Datas
Source Biochem Pharmacol (2015). GSK1120212, Figure 5. (Abmole Bioscience Kowloon, Hong Kong, China)
Method western blot
Cell Lines CD4+ T cells
Concentrations 20 mM
Incubation Time 24 h
Results Addition of GSK1120212, an inhibitor of MEK to the growth media diminished phosphorylation of ERK, but showed no noticeable effect on the inhibition of arctigenin against mTORC1 activation (Fig. 5D).
Rating
Source J Bio Chem (2014). Figure 9. GSK1120212 (AbMole BioScience).
Method Rats in the inhibitor groups were treated with GSK1120212
Cell Lines
Concentrations 0.3 mg/kg
Incubation Time
Results In animals receiving GSK1120212, shockwave treatment did not significantly change the percentage of Ki-67 or phospho-Erk1/2 positive cells (Figure 9B and C). These data support our findings that ischemic wound healing in shockwave treated animals is significantly enhanced by shockwave treatment and is dependent on Erk1/2 pathways.
Rating
Source J Bio Chem (2014). Figure 8. GSK1120212 (AbMole BioScience).
Method Rats in the inhibitor groups were treated with GSK1120212
Cell Lines
Concentrations
Incubation Time
Results "Planimetric analysis of the wound size area on the ischemic side of the epigastric flap was performed immediately after surgery (day 0) and on days 1, 5, and 10 after surgery (Figure 8C and D) Shockwave treatment of the ischemic side of the epigastric flap (100 pulses at 0.13 mJ/mm2) significantly decreased the wound size compared to control animals (Figure 8A). In animals receiving the Mek1/2 inhibitor GSK1120212 (0.1 mg/kg daily), wound sizes in the control and shockwave groups did not differ (Figure 8B). These results suggest that shockwave treatment exerts its beneficial effects on wound healing by induction of Erk1/2 signaling."
Rating
Source Biochemical Pharmacology (2015). Figure 7. LY294002, MK-2206 and GSK1120212 were gifts from Abmole Bioscience (Kowloon, Hong Kong).
Method Western blot
Cell Lines Purified CD4+ T cells
Concentrations 20 mM LY294002, 10 mM MK-2206 as well as 10 mM GSK1120212
Incubation Time 3 h
Results Arctigenin could inhibit mTORC1 activation via a way independent of PI3K/AKT and ERK.
Rating
Source J. Biol. Chem (2015). Figure 1. GSK1120212 (AbMole BioScience)
Method IHC
Cell Lines none
Concentrations 0.1 mg/kg daily
Incubation Time 10 days
Results Ischemic wound healing in shockwave treated animals is significantly enhanced by shockwave treatment and is dependent on Erk1/2 pathways.
Rating
Source J. Biol. Chem (2015). Figure 8. GSK1120212 (AbMole BioScience)
Method shockwave treatment in vivo
Cell Lines control
Concentrations 0.1 mg/kg daily
Incubation Time 10 days
Results Shockwave treatment enhances wound healing in a rat model by promoting proliferation via Erk1/2 signaling
Rating
Product Citations
References

Combination Small Molecule MEK and PI3K Inhibition Enhances Uveal Melanoma Cell Death in a Mutant GNAQ- and GNA11-Dependent Manner.
Khalili JS et al. Clin Cancer Res. 2012 Aug 15;18(16):4345-55. PMID: 22733540.

Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212.
Jing J et al. Mol Cancer Ther. 2012 Mar;11(3):720-9. PMID: 22169769.

Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo.
Yamaguchi T et al. Int J Oncol. 2011 Jul;39(1):23-31. PMID: 21523318.

GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition.
Gilmartin AG et al. Clin Cancer Res. 2011 Mar 1;17(5):989-1000. PMID: 21245089.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: GSK1120212, JTP-74057, GSK212 supplier, MEK, inhibitors

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