PD184352 (CI-1040)

製品コードS1020 バッチS102002

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C17H14ClF2IN2O2
分子量 478.67 CAS No. 212631-79-3
Solubility (25°C)* 体外 DMSO 96 mg/mL (200.55 mM)
Ethanol 14 mg/mL (29.24 mM)
Water Insoluble
体内 （毎回新しく調製した物を用意してください）
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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 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. PD184352 (CI-1040) selectively induces apoptosis.
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]
特徴 First MEK inhibitor to begin clinical development.

プロトコル(参考用のみ)

キナーゼアッセイ 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.
細胞アッセイ 細胞株 Colon 26 carcinoma cells
濃度 0.1-10 μM
反応時間 24 hours
実験の流れ

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.
動物実験 動物モデル PTC cells in athymic mice
投薬量 150 mg/kg
投与方法 Orally twice daily

参考

  • 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/

カスタマーフィードバック

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

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

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

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GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer [ Nat Commun, 2024, 15(1):2132] PubMed: 38459011
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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
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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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