Antibodies
PD0325901
- 貨號 Cat. No.
- S1036
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
PD0325901
Licensed by Pfizer
PD0325901 (PD325901) is selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. Phase 1/2.
| Size | Price | Stock | Quantity | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||
Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | PD0325901 (PD325901) is selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. Phase 1/2. | |||||
|---|---|---|---|---|---|---|
| Targets | MEK | |||||
| IC50 | 0.33 nM [1] | |||||
| 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:
| 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:
| 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:
| Animal Models | Ncr-nu/nu mice bearing PTC cells |
|---|---|
| Dosages | 20-25 mg/kg |
| Administration | Oral gavage |
| Solubility | 30% PEG400/0.5% Tween80/5% propylene glycol, 8 mg/mL |
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT00147550 | Terminated | Melanoma|Colonic Neoplasms|Breast Neoplasms | Pfizer | 2004-02 | Phase 1|Phase 2 |
| NCT00174369 | Terminated | Carcinoma, Non-Small-Cell Lung | Pfizer | 2005-11 | Phase 2 |
| NCT01347866 | Recruiting | Advanced Cancer | Pfizer | 2011-10 | Phase 1 |
Chemical Information
| Molecular Weight (MW) | 482.19 |
|---|---|
| Formula | C16H14F3IN2O4 |
| CAS No. | 391210-10-9 |
| Storage | 3 years -20℃Powder |
|---|---|
| 6 months-80℃in DMSO | |
| Syonnyms | N/A |
| Solubility (25°C) * | In vitro | DMSO | 96 mg/mL (199 mM) |
|---|---|---|---|
| Water | <1 mg/mL (<1 mM) | ||
| Ethanol | 40 mg/mL (82 mM) | ||
| In vivo | 30% PEG400/0.5% Tween80/5% propylene glycol, | 8 mg/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 |
|---|
Preparing Stock Solutions
| Stock Solution (1ml DMSO) | 1mM | 10mM | 20mM | 30mM |
|---|---|---|---|---|
| Mass(mg) | 0.48219 | 4.8219 | 9.6438 | 14.4657 |
Customer Reviews (9)
 Click to enlarge | 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. |
Product Citations (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]
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]
Adaptive informatics for multifactorial and high-content biological data. [Millard BL, et al. Nat Methods 2011;8(6):487-93]
