Antibodies
PD184352 (CI-1040)
- 貨號 Cat. No.
- S1020
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
PD184352 (CI-1040)
CI-1040 (PD 184352) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM, 100-fold more selective for MEK1/2 than MEK5. Phase 2.
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Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | CI-1040 (PD 184352) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM, 100-fold more selective for MEK1/2 than MEK5. Phase 2. | |||||
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| Targets | MEK1 | MEK2 | ||||
| IC50 | 17 nM | 17 nM [1] | ||||
| In vitro | CI-1040 treatment produces a reduction of pMAPK levels in multiple tumor cells including Colon 26, BX-PC3 pancreatic, A431 cervical, HT-29 colon, ZR-25-1 breast and SKOV-3 ovarian carcinomas. CI-1040 treatment doesn’t inhibit the phosphorylation of Jun kinase, p38 kinase or Akt, indicating CI-1040 specifically targets MEK. Inhibition of MAPK activation by CI-1040 prevents cell cycle progression and induces a G1 block. [1] The IC50 for inhibition of MEK1 by CI-1040 is 0.3 μM, 15-fold higher than the concentration required to inhibit the EGF-induced activation of ERK2 in Swiss 3T3 cells. These results indicate CI-1040 exerts its effects on cells by suppressing the activation of MKK1, and not by blocking its activity. 2 nM PD184352 inhibits the activation of MKK1 in Swiss 3T3 cells by 50%, while over 100-fold concentration of CI-1040 inhibits MEK1 in vitro. PD184352 also inhibits the Raf-catalysed phosphorylation of MEK1 without any effect on the Raf-catalysed phosphorylation of myelin basic protein. [2] CI-1040 inhibits 86% of papillary thyroid carcinoma (PTC) cell growth with the RET/PTC1 rearrangement at 10μM compared with cells treated with DMSO only. CI-1040 shows potent inhibition to PTC cells (BRAF mutation) with GI50 of 52 nM, but low activity to RET/PTC1 rearrangement type with GI50 of 1.1 μM. [3] A recent research indicates CI-1040 increases the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. [4] | |||||
| In vivo | Oral dosing of CI-1040 impairs the growth of colon tumor xenografts of mouse and human with a wide dose range of 48-200 mg/kg per dose, but not of P388 leukemia. [1] CI-1040 inhibits the tumor xenografts from PTC cells carrying a BRAF mutation with 31.3% reduction, carrying the RET/PTC1 rearrangement with 47.5% reduction than in untreated (vehicle) mice after 3 weeks of oral administration (300 mg/kg/d). No toxic effects are observed in any mice when they are treated with CI-1040. [2] Transient exposure of mammary tumors to CI-1040 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth. Combined treatment with CI-1040 (25 mg/kg) and UCN-01 (0.1-0.2 mg/kg) significantly reduces MDA-MB-231, and largely abolishs MCF7 tumor growth in implanted athymic mice, while either single treatment has no significant activity. The drug combination leads to profound tumor cell death which correlates with a reduction in the phosphorylation of ERK1/2 and the immuno-reactivity of Ki67 and of CD31. [5] | |||||
| Features | First MEK inhibitor to begin clinical development. | |||||
Protocol(Only for Reference)
Kinase Assay:
| MEK1 Assay | MAP kinase is activated after phosphorylation by MEK; the activated MAP kinase subsequently phosphorylates myelin basic protein (MBP).Incorporation of 32P into myelin basic protein (MBP) is assayed in the presence of glutathione S-transferase (GST) fusion proteins containing the 44-kDa MAPK (GST-MAPK) or the 45-kDa MEK (GST-MEK1). Assays are conducted in 50μL of 50 mM Tris, pH 7.4/10 mM MgCl2 /2 mM EGTA/10 μM [γ-32P]ATP containing 10 μg of GST-MEK1, 0.5 μg of GST-MAPK, and 40 μg of MBP. After incubation at 30°C for 15 minutes, reactions are stopped by addition of Laemmli SDS sample buffer. Phosphorylated MBP is resolved by SDS/10% PAGE. This screening effort leads to the discovery of several small-molecule inhibitors of MEK, i.e. CI-1040. Experiments assessing the order of addition shows that CI-1040 directly inhibits MEK1 with a 50% inhibitory concentration (IC50) of 17 nM, without affecting the activity of MAPK. |
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Cell Assay:
| Cell lines | Colon 26 carcinoma cells |
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| Concentrations | 0.1-10 μM |
| Incubation Time | 24 hours |
| Method | Cells are planted seeded in T-75 cm 2 flasks and treated the next day for 24 hous with either DMSO or CI-1040. Single-cell suspensions are collected, and pellets are fixed in ice-cold ethanol (70%) for 30 minutes. After centrifugation of the samples, propidium iodide (50 μg/mL) and RNase (30 units/mL) are added to the pellets for 20 minutes at 37 °C. After filtration, samples are analyzed by flow cytometry. |
Animal Study:
| Animal Models | PTC cells in athymic mice |
|---|---|
| Dosages | 150 mg/kg |
| Administration | Orally twice daily via p.o. |
| Solubility | 30% PEG400/0.5% Tween80/5% propylene glycol, pH 9 10 mg/mL |
References
Chemical Information
Download PD184352 (CI-1040) SDF
| Molecular Weight (MW) | 478.67 |
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| Formula | C17H14ClF2IN2O2 |
| CAS No. | 212631-79-3 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | N/A |
| Solubility (25°C) * | In vitro | DMSO | 96 mg/mL (200 mM) |
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| Water | <1 mg/mL (<1 mM) | ||
| Ethanol | 14 mg/mL (29 mM) | ||
| In vivo | 30% PEG400/0.5% Tween80/5% propylene glycol, pH 9 | 10 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 | 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide |
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Preparing Stock Solutions
| Stock Solution (1ml DMSO) | 1mM | 10mM | 20mM | 30mM |
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| Mass(mg) | 0.47867 | 4.7867 | 9.5734 | 14.3601 |
Customer Reviews (12)
 Click to enlarge | Rating | |
| Source | SCIENCE 2011 331, 912-916. PD184352 (CI-1040) purchased from Selleck | |
| Method | Immunohistochemistry | |
| Cell Lines | Hand2d/d mice | |
| Concentrations | ||
| Incubation Time | 24h | |
| Results | The epithelia of vehicle-treated horn showed prominent expression of p-FRS2 and p-ERK1/2(Fig.A,a and c). However, the levels of both p -FRS2 and p -ERK1/2 were reduced in the epithelia of PD173074-treated horn on day 4 of pregnancy (Fig. A, b and d). We also observed a marked decline in the proliferative activity of Hand2-null uterine epithelia, as indicated by decreased Ki-67 staining (Fig. A, e and f) . In parallel experiments, administration of PD184352, an inhibitor of the ERK1/2 pathway, to uterine horns of Hand2 d/d mice suppressed the level of pERK1/2 (Fig.B, a and b) , as well as luminal epithelial proliferation ( Fig. B, c and d).The ERK1/2-dependent phosphorylation of epithelial ERα at Ser118 is critical for the transcriptional activation of ERα. Administration of either PD173074 (Fig. C, a to d) or PD184352 (Fig. C, e to h) to Hand2-null uterine horns blocked the phosphorylation of epithelial ERα at Ser118 and the expression of Muc -1. |
Product Citations (27)
Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. [Nikolaev SI, et al. Nat Genet 2011;44(2):133-9]
The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. [Li Q, et al. Science 2011;331(6019):912-6]
Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation. [Guma M, et al. J Exp Med 2011;208(9):1889-900]
