CI-1040 (PD184352)

CI-1040 (PD 184352) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM.

Catalog No.S1020
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CI-1040 (PD184352) Chemical Structure

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

Validation & Quality Control

Customer Reviews(12)

Quality Control & MSDS

Related Compound Libraries

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

Product Information

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  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description CI-1040 (PD 184352) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM.
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]
Clinical Trials Currently under Phase II in breast cancer, colorectal cancer, lung cancer, and pancreatic cancer.
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.
1

References

Chemical Information

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

C17H14ClF2IN2O2

CAS No. 212631-79-3
Synonyms N/A
Solubility (25°C)
  • DMSO 96 mg/mL
  • Water <1 mg/mL
  • Ethanol 14 mg/mL
Storage 2 years -20°CPowder
2 weeks4°Cin DMSO
6 months-80°Cin DMSO
Chemical Name 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide

Research Area

Customer Reviews (12)


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Source SCIENCE, 2011, 331, 912-916. CI-1040 (PD184352) 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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Source J Natl Cancer Inst, 2012, 104(21), 1673-9. CI-1040 (PD184352) 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. CI-1040 (PD184352) 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(39), 16392-7.. CI-1040 (PD184352) 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 Neoplasia, 2011, 13, 154–166. CI-1040 (PD184352) 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 Dr Zhang of Tianjin Medical University. CI-1040 (PD184352) 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 Breast Cancer Res, 2011, 13, R36. CI-1040 (PD184352) 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 Dr Zhang of Tianjin Medical University. CI-1040 (PD184352) 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 Dr Shuo Dong of Baylor College of Medicine. CI-1040 (PD184352) purchased from Selleck
Method Cell colony formation assays
Cell Lines primary hematopoietic cells
Concentrations 10 μM
Incubation Time
Results

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Rating
Source Neoplasia, 2011, 13, 154–166. CI-1040 (PD184352) 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. CI-1040 (PD184352) 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 Breast Cancer Res, 2011, 13, R36. CI-1040 (PD184352) 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).

Product Citations (22)

  • Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. [Nikolaev SI, et al. Nat Genet 2011;44(2):133-9]

    PubMed: 22197931
  • The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. [Li Q, et al. Science 2011;331(6019), 912-916]

    PubMed: 21330545
  • 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]

    PubMed: 21825016
  • HER2 overcomes PTEN (loss)-induced senescence to cause aggressive prostate cancer. [Ahmad I, et al. Proc Natl Acad Sci U S A 2011;108(39):16392-7]

    PubMed: 21930937
  • RSK promotes G2 DNA damage checkpoint silencing and participates in melanoma chemoresistance. [Ray-David H, et al. Oncogene 2012;ahead of print]

    PubMed: 23108403
  • BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. [Corcoran RB, et al. Sci Signal 2010;3(149), ra84]

    PubMed: 21098728
  • Cross-regulation between FOXA1 and ErbB2 signaling in estrogen receptor-negative breast cancer. [Naderi A, et al. Neoplasia 2012;14(4):283-96]

    PubMed: 22577344
  • Synergy between inhibitors of androgen receptor and MEK has therapeutic implications in estrogen receptor-negative breast cancer. [Naderi A, et al. Breast Cancer Res 2011;13(2), R36]

    PubMed: 21457548
  • A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer. [Chia KM, et al. Neoplasia 2011;13(2), 154-166]

    PubMed: 21403841
  • Ras mutation cooperates with β-catenin activation to drive bladder tumourigenesis. [Ahmad I, et al. Cell Death Dis 2011;2:e124]

    PubMed: 21368895
  • Prolactin-induced protein mediates cell invasion and regulates integrin signaling in estrogen receptor-negative breast cancer. [Naderi A, et al. Breast Cancer Res 2012;14(4):R111]

    PubMed: 22817771
  • Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects. [Runtuwene V, et al. Dis Model Mech 2011;4(3):393-9]

    PubMed: 21263000
  • Endothelial Nitric Oxide Synthase Activation Generates an Inducible Nitric Oxide Synthase-Like Output of Nitric Oxide in Inflamed Endothelium. [Lowry JL, et al. J Biol Chem 2012;ahead of print]

    PubMed: 23255592
  • Acidosis promotes Bcl-2 family-mediated evasion of apoptosis: involvement of acid-sensing G protein-coupled receptor Gpr65 signaling to Mek/Erk. [Ryder C, et al. J Biol Chem 2012;287(33):27863-75]

    PubMed: 22685289
  • Cigarette smoke components induce matrix metalloproteinase-1 in aortic endothelial cells through inhibition of mTOR signaling. [Lema顃re V, et al. Toxicol Sci 2011;123(2):542-9]

    PubMed: 21742783
  • Research Resource: Identification of Novel Growth Hormone-Regulated Phosphorylation Sites by Quantitative Phosphoproteomics. [Ray BN, et al. Mol Endocrinol 2012;26(6):1056-73]

    PubMed: 22570334
  • Antiviral activity of the MEK-inhibitor U0126 against pandemic H1N1v and highly pathogenic avian influenza virus in vitro and in vivo. [Droebner K, et al. Antiviral Res 2011;92(2), 195-203]

    PubMed: 21854809
  • Molecular characterisation of MEK1/2- and MKK3/6-like mitogen-activated protein kinase kinases (MAPKK) from the fox tapeworm Echinococcus multilocularis. [Gelmedin V, et al. Int J Parasitol 2012;40(5), 555-567]

    PubMed: 19887070
  • Arf6 promotes cell proliferation via the PLD-mTORC1 and p38MAPK pathways. [Knizhnik AV, et al. J Cell Biochem 2012;113(1):360-71]

    PubMed: 21928324
  • Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. [Ercan D, et al. Cancer Discov 2012;2(10), 934-947]

    PubMed: 22961667
  • Detection of Allosteric Kinase Inhibitors by Displacement of Active Site Probes. [Lebakken CS, et al. J Biomol Screen 2012;17(6):813-21]

    PubMed: 22453235
  • Measurement of TLR-Induced Macrophage Spreading by Automated Image Analysis: Differential Role of Myd88 and MAPK in Early and Late Responses. [Wenzel J, et al. Front Physiol 2011;2, 71]

    PubMed: 22028692

Tech Support & FAQs

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