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CI-1040

CI-1040 (PD 184352) 是一种有口服活性的高度特异性MEK 小分子抑制剂，对 MEK1 的IC50值为 17 nM 。

CAS号

212631-79-3

分子式

C17H14ClF2IN2O2

主要靶点

MEK|Apoptosis

仅限科研使用

Cat No : CM05059

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Synonyms

PD 184352

验证数据展示

  • CAS No.: 212631-79-3

    CI-1040
    CAS#: 212631-79-3

产品信息

CI-1040 (PD184352) is an ATP non-competitive MEK1/2 inhibitor (IC50: 17 nM).

CAS号 212631-79-3
分子式 C17H14ClF2IN2O2
主要靶点 MEK|Apoptosis
主要通路 MAPK信号通路|凋亡
分子量 478.67
纯度 99.10%， 此纯度可做参考，具体纯度与批次有关系，可咨询客服
储存条件 Powder: -20°C for 3 years | In solvent: -80°C for 1 year
别名 PD 184352

靶点活性

MEK1:17 nM (cell free)|MEK2:17 nM (cell free)

体内活性

The tumors were excised at 1 hour and 6 hours after treatment with PD 184352 (150 mg/kg, i.p. or p.o.). Treatment with PD 184352 completely suppressed MAPK phosphorylation by either route of administration for at least 6 hours. MAPK phosphorylation returned at 12 hours after dosing and attained control levels by 24 hours [1]. In vivo, the systemic administration of the MEK inhibitor CI-1040 reduced adenoma formation to a third and significantly restored lung structure. The proliferation rate of lung cells of mice treated with CL-1040 was decreased without any obvious effects on the differentiation of pneumocytes [4].

体外活性

PD 184352 (CI-1040) also substantially reduced steady-state levels of phosphorylated MAPK (pMAPK) in a diverse panel of tumor lines grown in the presence of serum. Treatment of colon 26 cells for 1 hour with 1 μM PD 184352 produced a reduction of pMAPK levels of more than 75%. Treatment of colon 26 cells with 10 μM PD 184352 did not inhibit the phosphorylation of Jun kinase, p38 kinase or AKT [1]. The IC50 for inhibition of MKK1 by PD 184352 was 0.3 μM, 15-fold higher than the concentration required to inhibit the EGF-induced activation of ERK2 in Swiss 3T3 cells. The activation of MKK1 in cells was inhibited by 50% at 2 nM PD 184352 [2]. CI-1040 induced apoptosis and inhibited proliferation in U-937 cells in a dose and time-dependent manner. CI-1040 induced a significant increase in PUMA mRNA and protein levels. Knockdown of PUMA by PUMA siRNA transfection inhibited CI-1040-induced apoptosis and proliferation inhibition in U-937 cells [3].

溶解度

Ethanol:12 mg/mL (25 mM),DMSO:47.9 mg/mL (100 mM)

细胞实验

Cells were planted seeded in T-75 cm2 flasks and treated the next day for 24 h with either DMSO or PD 184352. Single-cell suspensions were collected, and pellets were fixed in ice-cold ethanol (70%) for 30 min. After centrifugation of the samples, propidium iodide (50 μg/ml) and RNase (30 units/ml) were added to the pellets for 20 min at 37 °C. After filtration, samples were analyzed by flow cytometry [1].

动物实验

Tumor fragments (approximately 3 mm^3 in size) were implanted subcutaneously into the right axillae of CD2F1 male mice (colon 26 studies) or female nude mice (HT-29 studies) 4–6 weeks old. Treatment was administered by gavage or intraperitoneally and was initiated either the day after tumor implantation (colon 26) or when tumors reached approximately 200 mg in size (HT-29). PD 184352 was prepared in a vehicle of 10% Cremophore EL, 10% ethanol and 80% water. Tumor size was evaluated periodically by caliper measurements, generally three times per week. Percent tumor growth inhibition was calculated as [(T–C)/number of days of treatment] × 100, with T and C being defined as the time required for treated and control tumors, respectively, to reach 750 mg (colon 26) or to reach twofold growth (HT-29) [1].

参考文献

1.Sebolt-Leopold JS, et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med. 1999 Jul;5(7):810-6.
2.Davies SP, et al. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
3.Wei CR, et al. MEK inhibitor CI-1040 induces apoptosis in acute myeloid leukemia cells in vitro. Eur Rev Med Pharmacol Sci. 2016 May;20(10):1961-8.
4.Kramer BW, et al. Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040strongly reduces growth and improves lung structure. BMC Cancer. 2004 Jun 1;4:24.

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