GSK1120212 (Trametinib)

Biological Activity

Product Citations

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  Immunobiology. 2023 Jan;228(1):152311.

  Characterization of the impact of immune checkpoint inhibitors on platelet activation and aggregation
  GSK1120212 (Trametinib) purchased from AbMole

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  Cancer Res Commun. 2022 Aug.

  Pharmacological inhibition of SHP2 blocks both PI3K and MEK signaling in low-epiregulin HNSCC via GAB1
  GSK1120212 (Trametinib) purchased from AbMole

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  Oncogene. 2020 Apr;39(15):3163-3178.

  The EGFR-ZNF263 Signaling Axis Silences SIX3 in Glioblastoma Epigenetically
  GSK1120212 (Trametinib) purchased from AbMole

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  Cancer Cell. 2018 Aug 16;pii: S1535-6108(18)30318-0.

  Identification of Therapeutic Targets in Rhabdomyosarcoma through Integrated Genomic, Epigenomic, and Proteomic Analyses.
  GSK1120212 (Trametinib) purchased from AbMole

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  Int J Mol Sci 2018 Jan 18;19(1) pii: E289.

  BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy
  GSK1120212 (Trametinib) purchased from AbMole

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  Biochem Pharmacol. 2015 Aug 15;323-36.

  Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.
  GSK1120212 (Trametinib) purchased from AbMole

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  J Biol Chem. 2014 Sep 26;289(39):27090-104.

  Shock wave treatment enhances cell proliferation and improves wound healing by ATP release-coupled extracellular signal-regulated kinase (ERK) activation.
  GSK1120212 (Trametinib) purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Cancer Cell (2018). Figure 5. Trametinib (Abmole Bioscience, Houston, USA)
	Method	oral gavage
	Cell Lines	Mice
	Concentrations	0.1 mg/kg
	Incubation Time	—
	Results	Mice treated with IRN + VCR had stable disease (SD), whereas mice treated with either palbociclib + trametinib or abemaciclib + trametinib exhibited progressive disease.

	Source	Int J Mol Sci (2018). Figure 5. GSK1120212 (AbMole BioScience, Houston, TX, USA)
	Method	vitro experiments
	Cell Lines	CAR-T cells
	Concentrations	30 nM
	Incubation Time	16 h
	Results	CAR-T cells in the conditions without inhibitor, with DMSO solvent control, with Vem alone, Tram alone, Dabra alone, and the combination Dabra + Tram

	Source	Int J Mol Sci (2018). Figure 4. GSK1120212 (AbMole BioScience, Houston, TX, USA)
	Method	vitro experiments
	Cell Lines	CAR-T cells
	Concentrations	30 nM
	Incubation Time	16 h
	Results	The presence of Vem alone, Tram alone,Cobi alone, Vem + Cobi, and Dabra + Tram, but not of Dabra alone seemed to reduce these quantities to approximately 50%.

	Source	Int J Mol Sci (2018). Figure 3. GSK1120212 (AbMole BioScience, Houston, TX, USA)
	Method	vitro experiments
	Cell Lines	CAR-T cells
	Concentrations	30 nM
	Incubation Time	16 h
	Results	The condition with Vem + Cobi was similarly inhibited as Vem alone, while the Dabra + Tram condition was significantly less inhibited

	Source	Int J Mol Sci (2018). Figure 2. GSK1120212 (AbMole BioScience, Houston, TX, USA)
	Method	vitro experiments
	Cell Lines	CAR-T cells
	Concentrations	30 nM
	Incubation Time	16 h
	Results	Incubation with the MEK inhibitors Tram and Cobi alone, but also the combination of Vem + Cobi reduced the CD25 upregulation approximately to 50%

	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).

	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.

	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."

	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.

	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.

	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

Protocol (for reference only)

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

Chemical Information

Molecular Weight	615.39
Formula	C26H23FIN5O4
CAS Number	871700-17-3
Solubility (25°C)	DMSO 30 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Khalili JS et al. Clin Cancer Res. Combination Small Molecule MEK and PI3K Inhibition Enhances Uveal Melanoma Cell Death in a Mutant GNAQ- and GNA11-Dependent Manner.

[2] Jing J et al. Mol Cancer Ther. Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212.

[3] Yamaguchi T et al. Int J Oncol. Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo.

[4] Gilmartin AG et al. Clin Cancer Res. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition.