PD184352 (CI-1040)

PD184352 (CI-1040) 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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PD184352 (CI-1040) Chemical Structure

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

Validation & Quality Control

Product Citations(35)

Customer Reviews(12)

Quality Control & MSDS

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

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    Combination Therapy

Product Description

Biological Activity

Description PD184352 (CI-1040) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM, 100-fold more selective for MEK1/2 than MEK5. Phase 2.
Targets MEK1 [1] MEK2 [1]
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]
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 via p.o.
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, pH 9, 10 mg/mL
* 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.

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

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km
Example

For example, to convert the dose of resveratrol used in a mouse (22.4 mg/kg) to a dose based on surface area for 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)

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 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 DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 96 mg/mL (200 mM)
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

Research Area

Customer Reviews (12)


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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.

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Rating
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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Rating
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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Rating
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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Rating
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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Rating
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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Rating
Source 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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Rating
Source 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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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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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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Rating
Source Proc Natl Acad Sci U S A, 2011, 108(39), 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 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

Product Citations (35)

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