Mirdametinib (PD0325901)

生物活性

Mirdametinib (PD0325901) 是一种选择性的，ATP非竞争性的MEK抑制剂，IC50为0.33 nM，对ERK1和ERK2磷酸化抑制作用比CI-1040强500倍左右。PF-0325901比另一种MEK抑制剂CI-1040具有更高的渗透率。与CI-1040相比，PD 0325901可以到达体系的更深层。PD0325901是非ATP竞争性的MAPK激酶MEK抑制剂，抑制鼠类结肠26细胞的MEK时IC50为0.33nM。此外，Mirdametinib还能维持干细胞多能状态。

使用AbMole产品发表的文献

• bioRxiv. 2023 Jun.

  Progesterone is an Inducement of Heritable Pulmonary Arterial Hypertension with BMPR2 Mutation

• Nature. 2022 Jul;607(7917):149-155.

  Deciphering the immunopeptidome in vivo reveals new tumour antigens

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

  Deciphering the tumor-specific immunopeptidome in vivo with genetically engineered mouse models

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

  The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer

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

  Extracellular Matrix Stiffness Regulates DNA Methylation by PKCα-Dependent Nuclear Transport of DNMT3L

• bioRxiv. 2021 Jul 1;450516.

  Deciphering the tumor-specific immunopeptidome in vivo with genetically engineered mouse models

• J Nucl Med. 2018 Nov 21.

  MEK inhibition induces therapeutic iodine uptake in a murine model of anaplastic thyroid cancer.

• 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.

• 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.

• 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

产品使用成果展示

	数据来源	Journal of Nuclear Medicine (2018 Nov). Figure 3. PD-325901 (AbMole Bioscience Inc.)
	方法	oral gavage
	细胞系/动物模型	single mutant BRAFV600E mice
	浓度	30 mg/kg
	处理时间	10 days
	实验结果	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.

	数据来源	Journal of Experimental & Clinical Cancer Research (2018). Figure 4. PD-325901 (Abmole Bioscience)
	方法	oral gavage
	细胞系/动物模型	BRAFV600E/PIK3CAH1047R double-mutant mouse
	浓度	5 mg/kg
	处理时间	10 days
	实验结果	While Pi3K inhibition did not induced any change in Slc7a5 transcript abundance, MEK inhibition induced more than 50% reduction.

	数据来源	Oncotarget (2017). PD-325901, Figure 4. (AbMole Bioscience, Hong-Kong, China)
	方法	Western blot
	细胞系/动物模型	ATC cell
	浓度	5 mg/kg
	处理时间	24 h
	实验结果	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).

	数据来源	Oncotarget (2017). PD-325901, Figure 3. (AbMole Bioscience, Hong-Kong, China)
	方法	Western blot
	细胞系/动物模型	ATC cell
	浓度
	处理时间	24 h
	实验结果	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).

	数据来源	Oncotarget (2017). PD-325901, Figure 2. (AbMole Bioscience, Hong-Kong, China)
	方法	apoptosis assay
	细胞系/动物模型	OCUT-2 cells
	浓度	100 nM
	处理时间	24 h
	实验结果	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).

	数据来源	Oncotarget (2017). PD-325901, Figure 1. (AbMole Bioscience, Hong-Kong, China)
	方法
	细胞系/动物模型	SW1736 and OCUT-2 cell lines
	浓度	100 nM, 20 nM, 4 nM, 0.8 nM, 0.16 nM
	处理时间	72 h
	实验结果	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).

实验参考

体外实验*
细胞系	ME1007, ME4405, ME4686,ME8959, ME10538, and ME13923 human melanoma cell lines
方法	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.
浓度	0.1–1000 nM
处理时间	24, 48 or 72 h

*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。

体内实验*
动物模型	M14 (BRAFV600E) and ME8959 (wtBRAF) cells bearing mice xenograft model
配制	0.5% hydroxypropyl methyl-cellulose plus 0.2% Tween 80
剂量	50 mg/kg per day
给药处理	oral gavage

*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。

化学性质

分子量	482.19
分子式	C16H14F3IN2O4
CAS号	391210-10-9
溶解性（25°C）	DMSO 76 mg/mL
储存条件	粉末型式       -20°C   3年；4°C   2年 溶于溶剂       -80°C   6个月；-20°C   1个月
运输方式	冰袋运输，根据产品的不同，可能会有相应调整。

储备液配制

*下述溶液配置方法仅为基于分子量计算出的理论值。不同产品在配置溶液前，需考虑其在不同溶剂中的溶解度限制。

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	2.0739 mL	10.3694 mL	20.7387 mL
5 mM	0.4148 mL	2.0739 mL	4.1477 mL
10 mM	0.2074 mL	1.0369 mL	2.0739 mL

不同实验动物依据体表面积的等效剂量转换表（参考来源于公开文献）

	小鼠	大鼠	兔	豚鼠	仓鼠	狗
重量 (kg)	0.02	0.15	1.8	0.4	0.08	10
体表面积 (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km 系数	3	6	12	8	5	20

动物 A (mg/kg) = 动物 B (mg/kg) ×	动物 B的Km系数
	动物 A的Km系数

例如，依据体表面积折算法，将化合物用于小鼠的剂量20 mg/kg 换算成大鼠的剂量，需要将20 mg/kg 乘以小鼠的K_m系数（3），再除以大鼠的K_m系数（6），得到化合物用于大鼠的等效剂量为10 mg/kg。

参考文献

[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.