PD0325901 Licensed by Pfizer

Catalog No.S1036

PD0325901 is a selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM in cell-free assays, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. Phase 2.

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PD0325901 Chemical Structure

PD0325901 Chemical Structure
Molecular Weight: 482.19

Validation & Quality Control

Cited by 86 publications:

14 customer reviews :

Quality Control & MSDS

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Product Information

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  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description PD0325901 is a selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM in cell-free assays, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. Phase 2.
Targets MEK [1]
(Cell-free assay)
IC50 0.33 nM
In vitro 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 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]
Features

Protocol(Only for Reference)

Kinase Assay:

[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.

Cell Assay:

[3]

Cell lines PTC cells
Concentrations 0.1 nM- 1 μM
Incubation Time 48 hours
Method

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.

Animal Study:

[3]

Animal Models Ncr-nu/nu mice bearing PTC cells
Formulation 80 mM citric buffer (pH 7)
Dosages 20-25 mg/kg
Administration Oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Barrett SD, et al. Bioorg Med Chem Lett, 2008, 18(24), 6501-6504.

[2] Judith SS, et al. Proc Amer Assoc Cancer Res.2004,45, Abstract #4003

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-25)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02510001 Recruiting Solid Tumour|Colorectal Cancer University of Oxford|Queens University, Belfast|Oxford Un  ...more University of Oxford|Queens University, Belfast|Oxford University Hospitals NHS Trust|Velindre NHS Trust|University Hospital, Antwerp|Hospital Vall dHebron|Hopital St Antoine, Paris|European Georges Pompidou Hospital|Pfizer|University of Turin, Italy|Belfast Health and Social Care Trust|Beaumont Hospital|European Commission November 2014 Phase 1
NCT02096471 Active, not recruiting Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PN University of Alabama at Birmingham June 2014 Phase 2
NCT02022982 Recruiting KRAS Mutant Non-Small Cell Lung Cancer|Solid Tumors Dana-Farber Cancer Institute January 2014 Phase 1|Phase 2
NCT02039336 Recruiting Colorectal Cancer The Netherlands Cancer Institute|Pfizer January 2014 Phase 1|Phase 2
NCT02297802 No longer available Prior Treatment With PD-0325901 With Ongoing Clinical Response Sharp HealthCare June 2013 Phase 1

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Chemical Information

Download PD0325901 SDF
Molecular Weight (MW) 482.19
Formula

C16H14F3IN2O4

CAS No. 391210-10-9
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 96 mg/mL (199.09 mM)
Ethanol 40 mg/mL (82.95 mM)
Water <1 mg/mL (<1 mM)
In vivo 30% PEG 400+5% Tween 80+ddH2O 10mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide

Customer Product Validation(14)


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Rating
Source Nature 2015 517(7534), 391-5. PD0325901 purchased from Selleck
Method Western blot
Cell Lines Metabolic
Concentrations 10 mg/kg
Incubation Time 5 days
Results PD0325901 caused a decrease in PPARc phosphorylation at S112 and S273, confirming the established role of ERKs in regulating S112 and strongly suggesting a new role in regulating S273 (refs 22-24).

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Rating
Source J Exp Med 2014 211(3), 395-404. PD0325901 purchased from Selleck
Method Immunofluorescence microscopy
Cell Lines Female C.B-17 SCID/beige mice
Concentrations 25 mg/kg
Incubation Time 3 days
Results Pharmacological inhibition of ERK1/2 with an MEK1/2 inhibitor (PD0325901) restored TNF-induced VCAM-1 mRNA and protein expression in mice treated with rapamycin.

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Source Cancer Res 2009 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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Source Oncogene 2015 10.1038/onc.2015.97. PD0325901 purchased from Selleck
Method Western blot
Cell Lines BCPAP, TPC-1, LOXIMVI, A375 cells
Concentrations 1-10 uM
Incubation Time 16 h
Results To this end, it chose PD0325901 (a MEK inhibitor), and tested their effects on DR5 expression in two thyroid cancer cell lines (BCPAP and TPC-1) and two melanoma cell lines (LOXIMVI and A375). At the tested concentration ranges (1–10 uM), all three agents decreased the levels of p-ERK1/2 in the four cancer cell lines, indicating the effective suppression of the Raf/MEK/ERK signaling. Correspondingly, it observed reduction of DR5 levels in these cell lines post exposure to these inhibitors. Moreover we examined the effects of PLX4032 and AZD6244 at sub-micromolar concentrations on DR5 expression and found that both agents at 0.25 and 0.5 uM effectively reduced the levels of p-ERK1/2 and DR5 indicating that these agents at low concentration ranges also suppress DR5 expression.

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Source J Bone Miner Res 2011 26, 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.

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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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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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Source J Bone Joint Surg Am 2015 96(14), e117. PD0325901 purchased from Selleck
Method Picro Sirius Red and Alcian Blue staining
Cell Lines Nf1-/- mice
Concentrations 10 mg/kg
Incubation Time 22 days
Results MEK inhibitor, PD0325901 was insufficient to rescue the Nf12/2 fracture model, although it could increase bone formation in combination with rhBMP-2.

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Rating
Source Bone 2014 59, 151-61. PD0325901 purchased from Selleck
Method histological analysis
Cell Lines MEKi treated mice
Concentrations 10 mg/kg
Incubation Time 10-21 days
Results Mice treated with MEKi after the establishment of the cartilaginoussoft callus (Late group, days 10-21) showed an increase in the amountof cartilage remaining. This cartilage appeared characteristicallyhypertrophic and mineralized.

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Source Stem Cells Dev 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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Source J Genet Genomics 2012 39, 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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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 2010 Dr Zhang of Tianjin Medical University. PD0325901 purchased from Selleck
Method Western blot
Cell Lines Breast cancer cells
Concentrations 0-10 nM
Incubation Time 24 h
Results

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Source 2010 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.

Tech Support

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