Mirdametinib (PD0325901)

Biological Activity

Product Citations

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  bioRxiv. 2023 Jun.

  Progesterone is an Inducement of Heritable Pulmonary Arterial Hypertension with BMPR2 Mutation
  Mirdametinib (PD0325901) purchased from AbMole

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  Nature. 2022 Jul;607(7917):149-155.

  Deciphering the immunopeptidome in vivo reveals new tumour antigens
  Mirdametinib (PD0325901) purchased from AbMole

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  Mol Biol Cell. 2022 Jul 1;33(8):mbcP22031008.

  Deciphering the tumor-specific immunopeptidome in vivo with genetically engineered mouse models
  Mirdametinib (PD0325901) purchased from AbMole

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  Cancer Cell. 2021 Oct 11;39(10):1342-1360.e14.

  The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer
  Mirdametinib (PD0325901) purchased from AbMole

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  Adv Healthc Mater. 2021 Aug;10(16):e2100821.

  Extracellular Matrix Stiffness Regulates DNA Methylation by PKCα-Dependent Nuclear Transport of DNMT3L
  Mirdametinib (PD0325901) purchased from AbMole

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  bioRxiv. 2021 Jul 1;450516.

  Deciphering the tumor-specific immunopeptidome in vivo with genetically engineered mouse models
  Mirdametinib (PD0325901) purchased from AbMole

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  J Nucl Med. 2018 Nov 21.

  MEK inhibition induces therapeutic iodine uptake in a murine model of anaplastic thyroid cancer.
  Mirdametinib (PD0325901) purchased from AbMole

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  J Exp Clin Cancer Res. 2018 Sep 21;37(1):234.

  The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model.
  Mirdametinib (PD0325901) purchased from AbMole

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  ChemMedChem. 2018 Dec 6.

  Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT-β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2.
  Mirdametinib (PD0325901) purchased from AbMole

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  Oncotarget. 2017 Apr 11;8(15):24604-24620.

  Combined MEK and Pi3’-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo
  Mirdametinib (PD0325901) purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Journal of Nuclear Medicine (2018 Nov). Figure 3. PD-325901 (AbMole Bioscience Inc.)
	Method	oral gavage
	Cell Lines	single mutant BRAFV600E mice
	Concentrations	30 mg/kg
	Incubation Time	10 days
	Results	The selective BRAFV600E inhibitor PLX-4720 did not increase Nis mRNA transcription, nor did the PI3K inhibitor GDC-0941 alone or in combination with PD-325901 or PLX-4720.

	Source	Journal of Experimental & Clinical Cancer Research (2018). Figure 4. PD-325901 (Abmole Bioscience)
	Method	oral gavage
	Cell Lines	BRAFV600E/PIK3CAH1047R double-mutant mouse
	Concentrations	5 mg/kg
	Incubation Time	10 days
	Results	While Pi3K inhibition did not induced any change in Slc7a5 transcript abundance, MEK inhibition induced more than 50% reduction.

	Source	Oncotarget (2017). PD-325901, Figure 4. (AbMole Bioscience, Hong-Kong, China)
	Method	Western blot
	Cell Lines	ATC cell
	Concentrations	5 mg/kg
	Incubation Time	24 h
	Results	Interestingly, PD-325901 treated mice presented a 40% tumor burden reduction after 6 weeks of treatment and remained stable for the rest of the experiment. Strikingly, the combination treated animals had a more pronounced response with a 60% tumor burden reduction after 7 weeks (Figure 4A). Interestingly, PD-325901 treated mice showed a clear improvement in histology with some almost normal follicles and smaller PTC areas. GDC-0941 did not induce a beneficial effect at the histological level. Finally, mice treated with the combination, although resulting in smaller sections, seemed to have a similar histological presentation to PD-325901 alone treated animals (Figure 4C).

	Source	Oncotarget (2017). PD-325901, Figure 3. (AbMole Bioscience, Hong-Kong, China)
	Method	Western blot
	Cell Lines	ATC cell
	Concentrations
	Incubation Time	24 h
	Results	ERK1/2 and AKT phosphorylation were assessed first to demonstrate the drug efficiency. ERK1/2 phosphorylation ratio (p-ERK1/2 normalized to total ERK) was strongly decreased in all cell lines when treated with PD-325901 alone or in combination with GDC-0941. Similarly, GDC-0941 induced a strong reduction of AKT phosphorylation ratio (Figure 3).

	Source	Oncotarget (2017). PD-325901, Figure 2. (AbMole Bioscience, Hong-Kong, China)
	Method	apoptosis assay
	Cell Lines	OCUT-2 cells
	Concentrations	100 nM
	Incubation Time	24 h
	Results	Only the OCUT-2 cell line already showed increased apoptosis (double positive annexinV and PI cells) when treated with the combination for 24 h (Figure 2A). However, after 48 h of combination treatment, all three cell lines (Figure 2B and Supplementary Figure 1) had elevated double positive annexinV/PI cells (late apoptosis) and annexinV positive cells (early apoptosis).

	Source	Oncotarget (2017). PD-325901, Figure 1. (AbMole Bioscience, Hong-Kong, China)
	Method
	Cell Lines	SW1736 and OCUT-2 cell lines
	Concentrations	100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM
	Incubation Time	72 h
	Results	We investigated the effect of the drugs on cell cycling. PD-325901 alone or in combination with GDC-0941 induced a G1 cycle arrest in SW1736 and 8505c cell lines. However, in OCUT-2, a significant effect was only observed for the combination (Figure 1C).

Protocol (for reference only)

Cell Experiment
Cell lines	ME1007, ME4405, ME4686,ME8959, ME10538, and ME13923 human melanoma cell lines
Preparation method	For IC50 assays, exponentially growing cells were exposed to increasing concentrations of PD0325901 (0.1–1000 nM) for 24, 48, or 72 hours. Cells were then assayed for cell viability (by trypan blue exclusion test) and counted using a Coulter Counter (Kontron Instruments, Milan, Italy). The IC50 value was calculated according to the Chou-Talalay method using the Calcusyn software.
Concentrations	0.1–1000 nM
Incubation time	24, 48 or 72 h

Animal Experiment
Animal models	M14 (BRAFV600E) and ME8959 (wtBRAF) cells bearing mice xenograft model
Formulation	0.5% hydroxypropyl methyl-cellulose plus 0.2% Tween 80
Dosages	50 mg/kg per day
Administration	oral gavage

Chemical Information

Molecular Weight	482.19
Formula	C16H14F3IN2O4
CAS Number	391210-10-9
Solubility (25°C)	DMSO 76 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] Torti et al. Mol Cancer Ther. Epithelial Tissue Hyperplasia Induced by the RAF Inhibitor PF-04880594 is Attenuated by a Clinically Well-Tolerated Dose of the MEK Inhibitor PD-0325901.

[2] Lee et al. PLoS One. A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells though MAPK activation.

[3] Simmons et al. Cancer Chemother Pharmacol. Combination of a MEK inhibitor at sub-MTD with a PI3K/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in Kras(G12D-LSL) mice.