PD184352 (CI-1040)

Catalog No.S1020

PD184352 (CI-1040) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM in cell-based assays, 100-fold more selective for MEK1/2 than MEK5. Phase 2.

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PD184352 (CI-1040) Chemical Structure

PD184352 (CI-1040) Chemical Structure
Molecular Weight: 478.67

Validation & Quality Control

Product Use Citation(42)

Customer Product Validation(12)

Quality Control & MSDS

Related Compound Libraries

PD184352 (CI-1040) is available in the following compound libraries:

MEK Inhibitors with Unique Features

Product Information

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  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description PD184352 (CI-1040) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM in cell-based assays, 100-fold more selective for MEK1/2 than MEK5. Phase 2.
Targets MEK1 [1]
(Cell-free assay)
MEK2 [1]
(Cell-free assay)
IC50 17 nM 17 nM
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]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
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... Click to View More Cell Line Experimental Data

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:

[2]

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.

Cell Assay:

[1]

Cell lines Colon 26 carcinoma cells
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:

[3]

Animal Models PTC cells in athymic mice
Formulation Cremophor EL–95% ethanol (50:50) and dilutes with water
Dosages 150 mg/kg
Administration Orally twice daily

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] Sebolt-Leopold JS, et al. Nat Med, 1999, 5(7), 810-816.

[2] Davies SP, et al. Biochem J, 2000, 135(1), 95-105.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-05-07)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00033384 Completed Breast Cancer|Colorectal Cancer|Lung Cancer|Pancreatic Cancer University of Alabama at Birmingham|National Cancer Insti  ...more University of Alabama at Birmingham|National Cancer Institute (NCI) February 2002 Phase 2
NCT00034827 Completed Colorectal Neoplasms|Breast Neoplasms|Carcinoma, Non-Small-Cell Lung|Pancreatic Neoplasms Pfizer January 2002 Phase 2

Chemical Information

Download PD184352 (CI-1040) SDF
Molecular Weight (MW) 478.67
Formula

C17H14ClF2IN2O2

CAS No. 212631-79-3
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 96 mg/mL (200.55 mM)
Ethanol 14 mg/mL (29.24 mM)
Water <1 mg/mL (<1 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

Customer Product Validation (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.

Click to enlarge
Rating
Source J Natl Cancer Inst 2012 104(21), 1673-9. PD184352 (CI-1040) purchased from Selleck
Method Western Blot
Cell Lines primary human melanocytes
Concentrations 1 uM
Incubation Time 18 h
Results In BRAFV600E melanoma cells, the highly selective BRAFV600E inhibitor GDC-0879 and three selective MEK inhibitors [PD184352/CI-1040, U0126, PD98059] did not suppress c-Jun levels, although they effectively reduced phospho-ERK levels.

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Rating
Source J Natl Cancer Inst 2012 104(21), 1673-9. PD184352 (CI-1040) purchased from Selleck
Method Xenograft
Cell Lines athymic nude Foxn1nu mice
Concentrations 3 mg/kg
Incubation Time 13 day
Results CDK2/4 inhibition augmented statistically significant growth reduction of melanoma xenografts in vivo by the BRAF and MEK inhibitors (GDC-0879 and CI1040).

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Source Proc Natl Acad Sci U S A 2011 108, 16392-7. PD184352 (CI-1040) purchased from Selleck
Method Western blot
Cell Lines DU145/PC3 cells
Concentrations 10 μM
Incubation Time 12 h
Results PI3K inhibition by LY294002 in-creased ERK activation in Her2-overexpressing DU145 cells, whereas treatment with the MEK inhibitor PD184352 in PC3 cells with Her2 overexpression resulted in increased AKT activation. This suggests a strong reciprocal feedback regulation of the PI3K/AKT and MEK/ERK signaling cascades (Fig. E)

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Source Breast Cancer Res 2011 13, R36. PD184352 (CI-1040) purchased from Selleck
Method MTT assay
Cell Lines MDA-MB-453 cell line, HCC-1954 cell line
Concentrations 2-25 μM
Incubation Time 48 h
Results We observed that monotherapies with CI-1040 and other inhibitors reduced cell viability in a dose-dependent manner across these cell lines

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Source Breast Cancer Res 2011 13, R36. PD184352 (CI-1040) purchased from Selleck
Method MTT assay/Western blot
Cell Lines MDA-MB-453-R cell line
Concentrations 5/10 μM
Incubation Time 48 h
Results "Flutamide and CI-1040 treatments were carried out at the same four dose combinations applied before in the nonresistant line (CI-1040(5μM)/flutamide(5μM), CI-1040 (10μM) /flutamide (5μM), CI-1040 (5μM)/flutamide (10μM), and CI-1040(10 μM)/f lutamide (10μM)). Importantly, we observed a synergy at all four dose combinations in MDA -MB-453-R line with CI values of 0.68 to 0.76 (Figure D). Combination therapies with CI-1040 (5μM)/f lutamide (5μM) and CI-1040 (5μM)/flutamide (10μM) completely abrogated ERK phosphorylationin MDA-MB-453-R line (Figure F).

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Source Neoplasia 2011 13, 154–166. PD184352 (CI-1040) purchased from Selleck
Method Western blot
Cell Lines MDA-MB-453 cell lines, HCC-1954 cell lines
Concentrations 10 μM
Incubation Time 24 h
Results We observed that CI-1040 at 10μM concentration almost completely inhibited ERK phosphorylation in both cell lines

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Source Neoplasia 2011 13, 154–166. PD184352 (CI-1040) purchased from Selleck
Method RT-PCR
Cell Lines MDA-MB-453 cell lines, HCC-1954 cell lines
Concentrations 10 μM
Incubation Time 24 h
Results We assessed AR expression using RT-PCR and observed a significant reduction of AR transcript level after MEK inhibition by CI-1040 to 0.2- and 0.6-fold in MDA-MB- 453 and HCC-1954 cells, respectively, compared with the controls (P < .01; Figure A). This finding suggest that ERK signaling regulates AR expression in molecular apocrine cells.

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Source Neoplasia 2011 13, 154–166. PD184352 (CI-1040) purchased from Selleck
Method MTT assay
Cell Lines MDA-MB-453 cell line, HCC-1954 cell line, HCC-202 cell line
Concentrations 5/10 μM
Incubation Time 48 h
Results These data suggest that AR inhibitor flutamide and MEK inhibit or CI-1040 have synergy in reducing cell viability of molecular apocrine cell lines.

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Source 2010 Dr. Zhang of Tianjin Medical University. PD184352 (CI-1040) purchased from Selleck
Method Western blot
Cell Lines Breast cancer cells
Concentrations 0-10 nM
Incubation Time 3 h
Results

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Source 2010 Dr. Zhang of Tianjin Medical University. PD184352 (CI-1040) purchased from Selleck
Method Western blot
Cell Lines Breast cancer cells
Concentrations 0-1 nM
Incubation Time 3 h
Results

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Source 2010 Dr. Shuo Dong of Baylor College of Medicine. PD184352 (CI-1040) purchased from Selleck
Method Cell colony formation assays
Cell Lines primary hematopoietic cells
Concentrations 10 μM
Incubation Time
Results

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