selleck产品在文献中的引用:
    
   
Clin Cancer Res,   2013, 19(20):5749-57
  
  
   
Cancer Res, 2013, 73(20):6346-58
  
  
   
PLoS One, 2013, 8(9):e73548
  
  
   
PLoS One, 2013, 8(10):e76505
  
  
   
Cancer Discov, 2013, 3(9):1058-71
  

使用Selleck产品的实验数据：

更多详情请访问中国唯一官方网站www.selleck.cn/products/CI-1040-(PD184352).html    
生物活性
产品描述
PD184352 (CI-1040)是一种ATP非竞争性的MEK1/2抑制剂，IC50为17 nM，对MEK1/2的选择性比MEK5高100倍。Phase 2。
靶点
MEK1
MEK2
 
 
 
 
IC50
17 nM
17 nM [1]
 
 
 
 
体外研究
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 doesnt 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]
体内研究
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]
临床实验
Currently under Phase II in breast cancer, colorectal cancer, lung cancer, and pancreatic cancer.
特征
First MEK inhibitor to begin clinical development.
推荐的实验操作(此推荐来自于公开的文献所以Selleck并不保证其有效性)
激酶实验: 
[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.
细胞试验: 
[1]
细胞系
Colon 26 carcinoma cells
浓度
0.1-10 μM
处理时间
24 hours
方法
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.
动物实验: 
[3]
动物模型
PTC cells in athymic mice
配制
Cremophor EL-95% ethanol (50:50) and dilutes with water
剂量
150 mg/kg
给药处理
Orally twice daily via p.o.
溶解度
30% PEG400/0.5% Tween80/5% propylene glycol, pH 9 10 mg/mL
参考文献
[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.
[3] Henderson YC, et al. Arch Otolaryngol Head Neck Surg, 2009, 135(4), 347-354
[4] Pellicano F, et al. Leukemia, 2011, 25(7), 1159-1167.
[5] Hawkins W, et al. Cancer Biol Ther, 2005, 4(11), 1275-1284.
[6] Legrier ME, et al, Cancer Res, 2007, 67(23), 11300-11308.
[7] Ou DL, et al, Clin Cancer Res, 2009, 15(18), 5820-5828.
[8] Jimeno A, et al, Mol Cancer Ther, 2007, 6(3), 1079-1088.