Mirdametinib

产品编号: T6189 别名:

PD0325901,PD325901

Mirdametinib 是一种选择性，非 ATP 竞争性和具有口服活性的MEK抑制剂，IC50为 0.33 nM。它抑制 p-ERK1/2 的表达并诱导细胞凋亡，具有抗癌活性。

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CAS：391210-10-9

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生物活性化学信息储存和溶解度信息参考文献引用文献

产品描述

PD0325901 is a specific and non-ATP-competitive MEK inhibitor (IC50: 0.33 nM).

体外活性

The 50% growth inhibition (GI50) by PD0325901 was 11 nmol/L for the PTC cells with the RET/PTC1 rearrangement and 6.3 nmol/L for PTC cells with a BRAF mutation, with both concentrations readily achievable in serum [2]. PD0325901 significantly increases aggregate cohesion, stiffness, and viscosity but only when tumor cells have access to high concentrations of fibronectin. Treatment also results in reorganization of actin from cortical into stress fibers, in both 2D and 3D culture [3]. On day 7 post-treatment (D14), the strongest effect in the cultures treated with a combination of ALK5 inhibitor SB431542 (2 μM) and MEK inhibitor PD0325901 (0.5 μM), which resulted in ~45 large ALP+ colonies with characteristic hESC-like morphology, of which over 24 colonies were TRA-1-81+, and about 6–10 colonies stained positive for SSEA4 and NANOG, a mature pluripotency factor that is not ectopically introduced [4].

体内活性

After 1 week of oral administration of PD0325901 (20–25 mg/kg/day) in mice, no tumor growth was detected in mice inoculated with PTC cells bearing a BRAF mutation. For PTC with the RET/PTC1 rearrangement, the average tumor volume of the orthotopic tumor was reduced by 58% as compared with controls [2].

激酶实验

Incorporation of 32P into myelin basic protein (MBP) is assayed in the presence of a glutathione S-transferase fusion protein containing p44MAP kinase (GST-MAPK) and a glutathione S-transferase protein containing p45MEK (GST-MEK). The assay solution contained 20 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM MnCl2, 1 mM EGTA, 50 mM [γ-32P]ATP, 10 mg GST-MEK, 0.5 mg GST-MAPK and 40 mg MBP in a final volume of 100 mL. Reactions are stopped after 20 minutes by addition of trichloroacetic acid and filtered through a GF/C filter mat. 32P retained on the filter mat is determined using a 1205 Betaplate [1].

细胞实验

A cell death detection enzyme-linked immunosorbent assay was used per the manufacturer's instructions. Briefly, 4 × 10^4 cells were plated in 24-well plates in triplicate the day before treatment. PTC cells were treated with 0.1 μmol/L PD0325901 for 96 hours. Cells treated with 1 μmol/L staurosporine served as positive controls for apoptosis. At the end of treatment, cells were lysed using the lysis buffer provided in the kit for 30 minutes at room temperature and then centrifuged in 24-well plates. Lysates (20 μL of supernatant) were transferred to streptavidin-coated wells and incubated for 2 hours at room temperature with two antibodies (biotin-labeled anti-histone antibody and peroxidase-conjugated anti-DNA antibody). After the wells were washed three times, the samples were incubated with peroxidase substrate (ABTS) and the amount of colored product was determined spectrophotometrically at 405 nm. The background was measured at 490 nm [2].

动物实验

Athymic Ncr-nu/nu mice were obtained from the National Cancer Institute at ages 6 to 8 weeks and housed for at least 1 week after arrival. Mice (10–14 per group) were anesthetized s.c. with a cocktail (100 μL/10 g body weight of 10 mg/mL ketamine and 1 mg/mL xylazine). K2 and TPC-1 cells stably infected with a retrovirus expressing luciferase (5 × 105 cells in 5 μL RPMI1640 medium) were inoculated into the thyroid gland, and the mice were monitored weekly for tumor growth by Xenogen (IVIS 200 imaging system) using Living Image 3.0 software. One week after inoculation, PD0325901 was dissolved in 80 mmol/L citric buffer (pH 7) by sonication and given to mice daily by oral gavage (20–25 mg/kg) for 3 weeks (5 consecutive days/week). Mice were sacrificed only due to tumor burden or loss of 20% of body weight. Tumor sizes were measured with calipers and tumor volume (V) was calculated by the formula (V = length × width × depth). Control mice were given 80 mmol/L citric buffer (pH 7) alone. All in vivo experiments were done at least twice [2].

Cas No.

391210-10-9

分子式

C16H14F3IN2O4

分子量

482.198

别名

PD0325901;PD325901;Mirdametinib

参考文献

[1]Lin T, et al. A chemical platform for improved induction of human iPSCs. Nat Methods. 2009 Nov;6(11):805-8.[2]Barrett SD, et al. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901. Bioorg Med Chem Lett. 2008 Dec 15;18(24):6501-4.[3]Chen F, Zhang M, Feng X, et al. Discovery of a Novel Long Noncoding RNA Lx8-SINE B2 as a Marker of Pluripotency[J]. Stem Cells International. 2021, 2021.[4]Li Y, He Y, Peng J, et al. Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer[J]. Nature Cancer. 2020: 1-17.[5]Guo Z, Kang S, Sun D, et al. MAPK-dependent hormonal signaling plasticity contributes to overcoming Bacillus thuringiensis toxin action in an insect host[J]. Nature Communications. 2020, 11(1): 1-14.[6]Shannon S, et al. Inhibition of glioblastoma dispersal by the MEK inhibitor PD0325901. BMC Cancer. 2017 Feb 10;17(1):121.[7]Henderson YC, et al. MEK inhibitor PD0325901 significantly reduces the growth of papillary thyroid carcinoma cells in vitro and in vivo. Mol Cancer Ther. 2010 Jul;9(7):1968-76.

引用文献

[1]Guo Z, Guo L, Qin J, et al. A single transcription factor facilitates an insect host combating Bacillus thuringiensis infection while maintaining fitness. Nature Communications. 2022, 13(1): 1-15.[2]Guo Z, Kang S, Sun D, et al. MAPK-dependent hormonal signaling plasticity contributes to overcoming Bacillus thuringiensis toxin action in an insect host. Nature Communications. 2020 Jun 12;11(1):3003. doi: 10.1038/s41467-020-16608-8.[3]Kuang, Junqi, et al. SS18 regulates pluripotent-somatic transition through phase separation.. Nature Communications. 2021 Jul 2;12(1):4090. doi: 10.1038/s41467-021-24373-5.[4]Wang W, Ren S, Lu Y, et al. Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2S production. The EMBO Journal. 2021 Jun 1;40(11):e106771. doi: 10.15252/embj.2020106771. Epub 2021 Apr 28.[5]Lin R, Zhai Z, Kuang J, et al. H3K27ac mediated SS18/BAFs relocation regulates JUN induced pluripotent-somatic transition. Cell & Bioscience. 2022, 12(1): 1-14 [6]Guo Z, Kang S, Wu Q, et al. The regulation landscape of MAPK signaling cascade for thwarting Bacillus thuringiensis infection in an insect host. PLoS pathogens. 2021, 17(9): e1009917.[7]Chen F, Zhang M, Feng X, et al. Discovery of a Novel Long Noncoding RNA Lx8-SINE B2 as a Marker of Pluripotency. Stem Cells International. 2021 Feb 6;2021:6657597. doi: 10.1155/2021/6657597. eCollection 2021.

储存和溶解度

H2O:Insoluble
DMSO:12.1 mg/mL (25 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years

剂量换算 Mirdametinib 391210-10-9

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Keywords

PD-0325901 MAPKK Mitogen-activated protein kinase kinase PD-325901 Apoptosis PD 0325901 MEK Autophagy Mirdametinib inhibit PD 325901 PD0325901 MAP2K PD325901 Inhibitor 391210-10-9

Mirdametinib 相关推荐

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Mirdametinib

PD0325901,PD325901

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