PD184352 (CI-1040)

Catalog No.S1020 Batch:S102001

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Technical Data

Formula

C17H14ClF2IN2O2
Molecular Weight 478.67 CAS No. 212631-79-3
Solubility (25°C)* In vitro DMSO 96 mg/mL (200.55 mM)
Ethanol 14 mg/mL (29.24 mM)
Water Insoluble
In vivo (Add solvents to the product individually and in order)
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

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. This compound selectively induces apoptosis.
Targets
MEK1 [1]
(Cell-free assay)		 MEK2 [1]
(Cell-free assay)
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. This compound treatment doesn't inhibit the phosphorylation of Jun kinase, p38 kinase or Akt, indicating it specifically targets MEK. Inhibition of MAPK activation by this chemical prevents cell cycle progression and induces a G1 block. [1] The IC50 for inhibition of MEK1 by this inhibitor 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 this agent exerts its effects on cells by suppressing the activation of MKK1, and not by blocking its activity. 2 nM this compound inhibits the activation of MKK1 in Swiss 3T3 cells by 50%, while over 100-fold concentration of it inhibits MEK1 in vitro. It also inhibits the Raf-catalysed phosphorylation of MEK1 without any effect on the Raf-catalysed phosphorylation of myelin basic protein. [2] This chemical inhibits 86% of papillary thyroid carcinoma (PTC) cell growth with the RET/PTC1 rearrangement at 10μM compared with cells treated with DMSO only. It 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 this agent 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] This compound 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 this chemical. [2] Transient exposure of mammary tumors to this compound and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth. Combined treatment with this chemical (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 (from 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. PD184352 (CI-1040). Experiments assessing the order of addition shows that this compound 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 this compound. 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

  • Dosages

    150 mg/kg

  • Administration

    Orally twice daily

References

  • https://pubmed.ncbi.nlm.nih.gov/10395327/
  • https://pubmed.ncbi.nlm.nih.gov/10998351/
  • https://pubmed.ncbi.nlm.nih.gov/19380355/
  • https://pubmed.ncbi.nlm.nih.gov/21483442/
  • https://pubmed.ncbi.nlm.nih.gov/16319524/
  • https://pubmed.ncbi.nlm.nih.gov/18056456/
  • https://pubmed.ncbi.nlm.nih.gov/19737956/
  • https://pubmed.ncbi.nlm.nih.gov/17363501/

Customer Product Validation

<p> </p><p>Melanoma cell viability and in vivo growth by cyclindependent kinase 2/4 inhibition. Western blot analysis for c-Jun, phosphorylated-ERK1/2 (Thr202/Tyr204) (p-ERK1/2), and total ERK1/2 protein levels was done for human melanoma cell lines treated with the BRAFV600E inhibitor GDC-0879 (1 μM), or MEK inhibitors CI-1040 (1 μM), U0126 (1 μM), and PD98059 (10 μM) for 18 hours.</p>

Data from [ J Natl Cancer Inst , 2012 , 104(21), 1673-9 ]

<p> </p><p>Melanoma cell viability and in vivo growth by cyclindependent kinase 2/4 inhibition. In vivo growth of LOXIMVI xenografts in athymic nude Foxn1nu mice is shown. Tumors were allowed to grow to a maximum volume of 250 mm3, and the mice were subsequently treated daily at the indicated dose levels with CDK2/4 inhibitors by intraperitoneal injection in combination with a BRAFV600E- or MEK-inhibitor. CDK2/4 inhibitor (CVT-313/indolocarbazole CDK4-I) treatment sensitizes tumors to GDC-0879 and CI1040.</p>

Data from [ J Natl Cancer Inst , 2012 , 104(21), 1673-9 ]

<p>The inhibitor PD173074 (A) or PD184352 (B) was administered to one uterine horn of Hand2d/d mice on day 3 of pregnancy (n = 5). The other horn served as vehicle-treated control. Uterine horns were collected on the morning of day 4, and sections were subjected to IHC to detect p-FRS2, p-ERK1/2, and Ki-67. (C) IHC of pERa and Muc-1 in uterine sections of Hand2d/d mice treated with PD173074 or PD184352.</p>

Data from [ Science , 2011 , 331, 912-916 ]

<p>LY294002 (10 μM for 12 h)- and PD184352 (10 μM for 12 h)-treated Her2-transfected DU145 and PC3 cells, respectively, showed reciprocal feedback inhibition between the PI3K/AKT and MEK/ERK path ways</p>

Data from [ Proc Natl Acad Sci U S A , 2011 , 108, 16392-7 ]

Selleck's PD184352 (CI-1040) Has Been Cited by 146 Publications

Transcriptional repressor Capicua is a gatekeeper of cell-intrinsic interferon responses [ Cell Host Microbe, 2025, 33(4):512-528.e7] PubMed: 40132591
Establishing Bovine Embryonic Stem Cells and Dissecting Their Self-Renewal Mechanisms [ Int J Mol Sci, 2025, 26(8)3536] PubMed: 40331984
Keratinocyte-derived VEGF-A is an essential pro-migratory autocrine mediator, acting through the KDR/GEF-H1/RhoA pathway [ Front Cell Dev Biol, 2025, 13:1601887] PubMed: 40746859
Inhibition of Retinoic Acid Receptor Gamma Improves Bovine Embryo Development [ Vet Sci, 2025, 12(10)924] PubMed: 41150070
GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer [ Nat Commun, 2024, 15(1):2132] PubMed: 38459011
eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations [ Proc Natl Acad Sci U S A, 2024, 121(44):e2321305121] PubMed: 39436655
Dietary protein restriction regulates skeletal muscle fiber metabolic characteristics associated with the FGF21-ERK1/2 pathway [ iScience, 2024, 27(3):109249] PubMed: 38450157
MEK1/2 inhibition decreases pro-inflammatory responses in macrophages from people with cystic fibrosis and mitigates severity of illness in experimental murine methicillin-resistant Staphylococcus aureus infection [ Front Cell Infect Microbiol, 2024, 14:1275940] PubMed: 38352056
Forchlorfenuron-Induced Mitochondrial Respiration Inhibition and Metabolic Shifts in Endometrial Cancer [ Cancers (Basel), 2024, 16(5)976] PubMed: 38473335
The NF-κB-HE4 axis: A novel regulator of HE4 secretion in ovarian cancer [ PLoS One, 2024, 19(12):e0314564] PubMed: 39621651

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