PD0325901

PD0325901は選択的です、そして、非ATP競争的有糸分裂促進物質はMEK活動のinhibitonのためにプロテインキナーゼ・キナーゼ(MEKまたはMAPKK)MEK阻害剤を起動させました。IC50 が 0.33 nMになる。

目録号S1036
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PD0325901 化学構造
分子量: 482.19

品質と確認

製品表彰状(44)

カスタマーレビュー(9)

Quality Control & MSDS

製品情報

  • Combination Therapy
    併用療法
  • Compare MEK Inhibitors
    MEK阻害剤を比較
  • 研究分野

製品の説明

生物活性

情報 PD0325901は選択的です、そして、非ATP競争的有糸分裂促進物質はMEK活動のinhibitonのためにプロテインキナーゼ・キナーゼ(MEKまたはMAPKK)MEK阻害剤を起動させました。IC50 が 0.33 nMになる。
目標

MEK

IC50

0.33 nM [1]

In vitro試験 PF0325901 shows higher permeability than CI-1040, another MEK inhibitor. PD0325901 should be able to achieve higher systemic exposures than CI-1040. [1] PD0325901 is exquisitely specific and highly potent against purified MEK, revealing a Kiapp of 1 nM against activated MEK1 and MEK2. [2] PD0325901 is roughly 500-fold more potent than CI-1040 with respect to its cellular effects on phosphorylation of ERK1 and ERK2, displaying subnanomolar activity. [2] PD0325901 prevents the growth of melanoma cell lines. PD0325901 inhibits the growth of TPC-1 cells and K2 cells with GI50 of 11 nM and 6.3 nM, respectively. [3] PD0325901 significantly prevents the the growth of PTC cells harboring a BRAF mutation at very low concentration (10 nM) and only moderately increases the growth of the PTC cells carrying the RET/PTC1 rearrangement at the same concentration. PD0325901 effectively inhibits the phosphorylation of ERK1/2 in multiple PTC cell lines. [3]
In vivo試験 The improved potency of PD0325901 relative to CI-1040 is evident. A single oral dose of PD0325901 (25 mg/kg) inhibits phosphorylation of ERK by more than 50% at 24 hours post-dosing. In contrast, CI-1040 at a much higher dose (150 mg/kg) only inhibit pERK levels for roughly 8 hours, returning to control levels by 24 hours after treatment. [2] Therefore, the dose required to produce a 70% incidence of complete tumor responses (C26 model) is 25 mg/kg/day versus 900 mg/kg/day for PD0325901 and CI-1040, respectively. Anticancer activity of PD 0325901 has been demonstrated for a broad spectrum of human tumor xenografts. [2] After 1 week of oral administration of PD0325901 (20–25 mg/kg/day) in mice, no tumor growth is detected in mice inoculated with PTC cells bearing a BRAF mutation. [3] For PTC with the RET/PTC1 rearrangement, the average tumor volume of the orthotopic tumor is decreased by 58% as compared with controls. In conclusion, PTC cells carrying a BRAF mutation are more sensitive to PD0325901 than are PTC cells carrying the RET/PTC1 rearrangement. [3]
臨床試験 Combined with PF-04691502/PF-05212384/CPT-11, PD-0325901 is currently in Phase I clinical trial for advanced cancer.
特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ:

[1]

In vitro cascade assay 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 [gamma-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. PD0325901 is assessed at various dose ranges in order to determine dose response curves.

細胞アッセイ:

[3]

細胞系 PTC cells
濃度 0.1 nM- 1 μM
処理時間 48 hours
方法

PTC cells (1 × 104) are seeded in 24-well plates with 1 mL of medium for 4 days in a 37 °C incubator. MEK inhibitor PD0325901 at varying concentrations is added to the cells in triplicate on day 0. MTT dissolved in 0.8% NaCl solution at 5 mg/mL is added to each well (0.2 mL) on day 2 to test GI50 or every day for cell growth curves. The cells are incubated at 37 °C for 3 hours with MTT. The liquid is then aspirated from the wells and discarded. Stained cells are dissolved in 0.5 mL of DMSO and their absorption at 570 nm is measured using a Synergy HT multidetection microplate reader. For GI50, cell growth is calculated as 100 × (T − T0)/(C − T0), where T is the optical density of the wells treated with inhibitors after a 48-hour period, T0 is the optical density at time zero, and C is the control optical density with DMSO only.

動物実験:

[3]

動物モデル Ncr-nu/nu mice bearing PTC cells
製剤 80 mM citric buffer (pH 7)
投薬量 20-25 mg/kg
管理 Oral gavage
1

参考

化学情報

Download PD0325901 SDF
分子量 482.19
化学式

C16H14F3IN2O4

CAS No. 391210-10-9
別名 N/A
溶解度 (25°C)
  • DMSO 96 mg/mL
  • 水 <1 mg/mL
  • エタノール 40 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO
化学名 (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide

研究分野

カスタマーレビュー (9)


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Rating
Source Cancer Res, 2009, 69, 6839-6847. PD0325901 purchased from Selleck
Method
Cell Lines
Concentrations 10 mg/kg
Incubation Time
Results "In all three tissues, the PD325901 compound blocks phosphorylation of ERK similarly. In contrast, RDEA119 exhibits tissue selectivity, showing little or no inhibition in brain, significantly lower effect in lung, and sustained efficacy in tumor tissue. The levels of RDEA119 in the lung are similar to the concentration in plasma, whereas the levels in the brain are much lower than in the plasma, suggesting that RDEA119 has low central nervous system (CNS) penetration. In contrast, concentrations of PD325901 are higher in the brain than in plasma.

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Rating
Source Breast Cancer Res, 2011, 13, R36. PD0325901 purchased from Selleck
Method Assessment of MEK inhibitor toxicity
Cell Lines MDA-MB-453 xenograft model
Concentrations 5/10/15/20 mg/kg/day
Incubation Time 30 days
Results We observed a significantly higher weight gain in mice treated with PD0325901 at 5 a nd 10 mg/kg/day doses compared to the control group( P <0.01, Figure A). Importantly, treatments with higher doses of PD0325901 at 15 and 20 mg/kg/day resulted in a significant weight reduction compared to the lower doses of this agent (P <0.01, Figure A). Furthermore, the number of treatment days lost due to toxicity was significantly lower with PD0325901 doses of 5 and 10 mg/kg/day compared to that of 15 and 20 mg/kg/day( P< 0.01, Figure 5B ). Notably, PD0325901 treatment at 5mg/kg/day did not result in any measurable toxicity using this approach (FigureA and B) . These findings indicate that PD0325901 treatment at lower doses is significantly less toxic than higher doses of this agent in a xenograft mouse model.

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Rating
Source Breast Cancer Res, 2011, 13, R36. PD0325901 purchased from Selleck
Method Immunohistochemistry
Cell Lines xenograft tumor
Concentrations
Incubation Time
Results Angiogenesis was significantly lower in the combination therapy group with a CD31-positive blood vessel count of 5.3 ± 3 compared to that of control (44± 6) and monotherapy groups (flutamide: 43 ± 7, PD0325901: 24 ± 7) (P < 0.03, Figure A to D ) . Moreover, CD-31- positive blood vessels in the combination therapy group were smaller and less distinct than those in other groups (Figure B to D).

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Rating
Source Journal of Genetics and Genomics 39 (2012) 643e651. PD0325901 purchased from Selleck
Method Rat embryoid bodies (rEBs) formation
Cell Lines rES cells
Concentrations 0.75 uM
Incubation Time 4 d
Results For the first 2 days of rEBs formation, rES cells were cultured in CM in the presence of Rho kinase inhibitor, Y-27632 (10 umol/L) and 2i (PD0325901, 0.1 umol/L; CHIR99021, 0.75 umol/L; Selleck, USA). Thereafter, we transferred the regular rEBs into CM supplemented with 2i and without Y-27632 for another 2 days. On day 4, abundant highquality rEBs formed and then 2i was eliminated from the media.

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Rating
Source STEM CELLS AND DEVELOPMENT, 2013. PD0325901 purchased from Selleck
Method Colony forming assay
Cell Lines iPS cells
Concentrations 2 uM
Incubation Time 18 day
Results To see if the addition of other small molecule inhibitors improves the efficacy of iPSC induction from myoblast cells in feeder-free conditions, ALK4/5/7 inhibitor SB431542 (SB), MEK inhibitor PD0325901 (PD), nonspecific GSK3 inhibitor lithium chloride (LiCl), and HDAC inhibitor VPA, all reported to enhance the efficiency of iPSC inductions, were tested in combination with NaB (Fig. 2C, D, and Supplementary Fig. S2). Addition of SB to the NaBcontaining medium enhanced the induction efficiency compared with NaB only. Further addition of PD or LiCl to the mixture did not further improve the efficiency.

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Rating
Source Dr Citrin.Deborah of NIH. PD0325901 purchased from Selleck
Method Western blot
Cell Lines HT29 Xenograft tumors
Concentrations 1 mg/kg
Incubation Time 24 h
Results Effects of PD0325901 on HT29 Xenograft tumors. PD0325901(1mg/kg carrier DMSO).Collection at 24h.

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Rating
Source Int J Proteomics, 2011, 2011, Article ID 215496. PD0325901 purchased from Selleck
Method Nikon inverted-phase microscope
Cell Lines lung tumor cell lines
Concentrations 0.1/1 µM
Incubation Time Two weeks
Results Proliferation of cell colony size in the H1734 cells was potently blocked by treatment with the downstream MEK inhibitor PD-325901 as seen when these cells were grown in cell culture.

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Rating
Source PD0325901 purchased from Selleck
Method Western blot
Cell Lines Breast cancer cells
Concentrations 0-10 nM
Incubation Time 24 h
Results

Click to enlarge
Rating
Source J Bone Miner Res, 2011, 26(10), 2486-2497. PD0325901 purchased from Selleck
Method qPCR analysis, Western blot
Cell Lines UMR-106 cells
Concentrations 100 nM
Incubation Time 3/24 h
Results To test for the dependence of MAPK signaling in the transcriptional regulation of Fgf23, we treated UMR-106 cells with the MEK inhibitor PD0325901 and the RAF inhibitor RAF265(Fig.B and D). We found that inhibition of MEK or RAF alone was not sufficient to fully block FGF9-mediated phosphorylation of ERK1/2 and the induction of Fgf23.

製品表彰状 (44)

  • MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. [Huang S, et al. Cell 2012;151(5):937-50]

    PubMed: 23178117
  • Decoupling of tumor-initiating activity from stable immunophenotype in HoxA9-Meis1-driven AML. [Gibbs KD Jr, et al. Cell Stem Cell 2012;10(2):210-7]

    PubMed: 22305570
  • Adaptive informatics for multifactorial and high-content biological data. [Millard BL, et al. Nat Methods 2011;8(6):487-93]

    PubMed: 21516115
  • Rapid phospho-turnover by receptor tyrosine kinases impacts downstream signaling and drug binding. [Kleiman LB, et al. Mol Cell 2011;43(5):723-37]

    PubMed: 21884975
  • Rapamycin antagonizes TNF induction of VCAM-1 on endothelial cells by inhibiting mTORC2 [Wang C J Exp Med 2014;10.1084/jem.20131125]

    PubMed: 24516119
  • Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. [Posch C , et al. Proc Natl Acad Sci U S A 2013;110(10):4015-20]

    PubMed: 23431193
  • RDEA119/BAY 869766: A potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. [Iverson C, et al. Cancer Res 2009;69(17):6839-47]

    PubMed: 19706763
  • Sensitivity of glioblastomas to clinically available MEK inhibitors is defined by neurofibromin 1 deficiency. [See WL, et al. Cancer Res 2012;72(13):3350-9]

    PubMed: 22573716
  • Attenuation of the Retinoblastoma Pathway in Pancreatic Neuroendocrine Tumors Due to Increased Cdk4/Cdk6. [Tang LH, et al. Clin Cancer Res 2012;18(17):4612-20]

    PubMed: 22761470
  • Early G1 cyclin-dependent kinases as prognostic markers and potential therapeutic targets in esophageal adenocarcinoma. [Ismail A, et al. Clin Cancer Res 2011;17(13):4513-22]

    PubMed: 21593195
  • BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. [Corcoran RB, et al. Sci Signal 2010;3(149):ra84]

    PubMed: 21098728
  • MicroSCALE screening reveals genetic modifiers of therapeutic response in melanoma. [Wood KC, et al. Sci Signal 2012;5(224):rs4]

    PubMed: 22589389
  • Activated MEK cooperates with Ink4a/Arf loss or Akt activation to induce gliomas in vivo. [Robinson JP, et al. Oncogene 2011;30(11):1341-50]

    PubMed: 21057530
  • Porcn-dependent Wnt signaling is not required prior to mouse gastrulation. [Biechele S, et al. Development 2013;140(14):2961-71]

    PubMed: 23760955
  • FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF23 signaling and regulating FGF23 expression in bone. [Wöhrle S, et al. J Bone Miner Res 2011;26(10):2486-97]

    PubMed: 21812026
  • Synergy between inhibitors of androgen receptor and MEK has therapeutic implications in estrogen receptor-negative breast cancer. [Naderi A, et al. Breast Cancer Res 2011;13(2):R36]

    PubMed: 21457548
  • A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer. [Chia KM, et al. Neoplasia 2011;13(2):154-66]

    PubMed: 21403841
  • CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, "fueling" tumor growth via paracrine interactions, without an increase in neo-angiogenesis. [Capparelli C, et al. Cell Cycle 2012;11(19):3599-610]

    PubMed: 22935696
  • A genomic approach to predict synergistic combinations for breast cancer treatment. [Soldi R, et al. Pharmacogenomics J 2013;13(1):94-104]

    PubMed: 22083351
  • Combined targeting of MEK/MAPK and PI3K/Akt signalling in multiple myeloma. [Steinbrunn T, et al. Br J Haematol 2012;159(4):430-40]

    PubMed: 22985491
  • The CDK4/6 inhibitor PD0332991 reverses epithelial dysplasia associated with abnormal activation of the Cyclin-CDK-Rb pathway. [Cabrera MC, et al. Cancer Prev Res (Phila) 2012;5(6):810-21]

    PubMed: 22508966
  • Cationic liposomal co-delivery of small interfering RNA and a MEK inhibitor for enhanced anticancer efficacy. [Kang SH, et al. Pharm Res 2011;28(12):3069-78]

    PubMed: 21879387
  • Germline Transmission of a Novel Rat Embryonic Stem Cell Line Derived from Transgenic Rats. [Men H, et al. Stem Cells Dev 2012;21(14):2606-12]

    PubMed: 22455749
  • Small Molecule Inhibitors Promote Efficient Generation of Induced Pluripotent Stem Cells From Human Skeletal Myoblasts. [Trokovic R, et al. Stem Cells Dev 2013;22(1):114-23]

    PubMed: 22671711
  • Met receptors induce Sam68-dependent cell migration by activation of alternate extracellular signal-regulated kinase family members. [Locatelli A, et al. J Biol Chem 2011;286(24):21062-72]

    PubMed: 21489997
  • Modulation of agrin-induced acetylcholine receptor clustering by extracellular signal-regulated kinases 1 and 2 in cultured myotubes. [Rimer M, et al. J Biol Chem 2010;285(42):32370-7]

    PubMed: 20696763
  • A sugar-based phase-transitioning delivery system for bone tissue engineering. [Cheng TL, et al. Eur Cell Mater 2013;26:208-21]

    PubMed: 24146213
  • Tumor reoxygenation following administration of Mitogen-Activated Protein Kinase inhibitors: A rationale for combination with radiation therapy. [Karroum O, et al. Radiother Oncol 2012;105(1):64-71]

    PubMed: 22682746
  • The extracellular-regulated protein kinase 5 (ERK5) promotes cell proliferation through the down-regulation of inhibitors of cyclin dependent protein kinases (CDKs). [Perez-Madrigal D, et al. Cell Signal 2012;24(12):2360-8]

    PubMed: 22917534
  • Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models. [Chiacchiera F, et al. Cancer Lett 2012;324(1):98-108]

    PubMed: 22579651
  • An integrative model links multiple inputs and signaling pathways to the onset of DNA synthesis in hepatocytes [Huard J, et al. FEBS J 2012;279(18):3290-313]

    PubMed: 22443451
  • Antiviral activity of the MEK-inhibitor U0126 against pandemic H1N1v and highly pathogenic avian influenza virus in vitro and in vivo. [Droebner K, et al. Antiviral Res 2011;92(2):195-203]

    PubMed: 21854809
  • Modulation of endochondral ossification by MEK inhibitors PD0325901 and AZD6244 (Selumetinib). [El-Hoss J, et al. Bone 2013;59:151-61]

    PubMed: 24269278
  • A Comparative Study of Protocols for Mouse Embryonic Stem Cell Culturing [Christoffer Tamm, et al. PLoS One 2013;8(12):e81156]

    PubMed: 24339907
  • An In Vivo C. elegans Model System for Screening EGFR-Inhibiting Anti-Cancer Drugs. [Bae YK, et al. PLoS One 2012;7(9):e42441]

    PubMed: 22957020
  • Derivation of a Germline Competent Transgenic Fischer 344 Embryonic Stem Cell Line. [Men H, et al. PLoS One 2013;8(2):e56518]

    PubMed: 23437152
  • The role of endosomal escape and mitogen-activated protein kinases in adenoviral activation of the innate immune response. [Smith JS, et al. PLoS One 2011;6(10):e26755]

    PubMed: 22046344
  • Serine-204 in the Linker Region of Smad3 Mediates the Collagen-I Response to TGF-β in a Cell Phenotype-Specific Manner. [Browne JA, et al. Exp Cell Res 2013;319(19):2928-37]

    PubMed: 24080014
  • Critical role of Shp2 in tumor growth involving regulation of c-Myc. [Ren Y, et al. Genes Cancer 2010;1(10):994-1007]

    PubMed: 21442024
  • Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells. [Chiaro C, et al. Biochem Biophys Res Commun 2012;428(1):121-6]

    PubMed: 23063976
  • Detection of Allosteric Kinase Inhibitors by Displacement of Active Site Probes. [Lebakken CS, et al. J Biomol Screen 2012;17(6):813-21]

    PubMed: 22453235
  • Generation of tripotent neural progenitor cells from rat embryonic stem cells. [Wang Z, et al. J Genet Genomics 2012;39(12):643-51]

    PubMed: 23273768
  • PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation. [Charytonowicz E, et al. Clin Transl Oncol 2012;14(3):197-206]

    PubMed: 22374423
  • Signatures of drug sensitivity in nonsmall cell lung cancer. [Gong HC, et al. Int J Proteomics 2011;2011:215496]

    PubMed: 22091388

技術サポート&よくある質問(FAQ)

顧客がするかもしれない質問に対する答えは、指示を取り扱っている阻害剤で見つかります。話題は、貯蔵液(阻害剤と特別な注意を細胞ベースの分析法と動物のために必要とする問題を保存することは実験します)を準備する方法を含みます。

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Related MEK 阻害剤

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    Selumetinib (AZD6244) は有効的にMEK1を抑制して、IC50 が14 nMになる.

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    PD184352 (CI-1040)は、ATP非競争MEK1/2阻害剤で、IC50 が 17 nMです。

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  • Pimasertib (AS-703026)

    Pimasertib (AS-703026) は非競争性阻害剤で、有効的に MEK1/2 を抑制して、IC50 が 5-11 nMになる.

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