Refametinib

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Chemical Structure| 923032-37-5 同义名 : 瑞美替尼 ;BAY 869766; RDEA119; BAY-69766
CAS号 : 923032-37-5
货号 : A151521
分子式 : C19H20F3IN2O5S
纯度 : 99%+
分子量 : 572.34
MDL号 : MFCD18633256
存储条件：

Pure form Keep in dark place, inert atmosphere, 2-8°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 30 mg/mL(52.42 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
生物活性
靶点

  • MEK2

    MEK2, IC50:47 nM

  • MEK1

    MEK1, IC50:19 nM
描述 MEKs, short for MAPK/ERK kinases, involve two isoforms of MEK1 and MEK2. MEKs act as an integration point for multiple biochemical signals. MEKs lie upstream of MAPK/ERK and stimulate the enzymatic activity of MAPK/ERK upon wide variety of extra- and intracellular signals. As an essential component of MAPK/ERK signal transduction pathway, MEKs are involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. Refametinib is an inhibitor of MEK1/2. Refametinib inhibited MEK activity with IC50 values of 19 nM and 47 nM for MEK1 and MEK2, respectively[3]. Refametinib potently inhibited phosphorylation of ERK1/2 across several human cancer cell lines with EC50 values ranging from 2.5 to 15.8 nM. Refametinib inhibited anchorage-dependent growth of human cancer cell lines with GI50 values ranging from 67 to 89 nM[3]. Refametinib also showed antiproliferative activity in HCC cell lines with IC50s ranging from 33 to 762 nM[4]. In an A375 tumor xenograft model established in nude mice, refametinib administrated orally at 25 or 50 mg/kg/d for 14 days inhibited 54% and 68% tumor growth, respectively. In a Colo205 tumor xenograft model established in nude mice, refametinib administrated orally at 2.5, 5, 10 or 25 mg/kg/d for 14 days inhibited 43%, 50%, 53% and 68% tumor growth, respectively[3]. In an orthotopic murine Hepa129 HCC allograft model, treatment by refametinib at the dose of 25 mg/kg once daily (reduced to 12.5 mg/kg since day18) resulted in median survival of 58 days, compared with 30 days for the control group[4].
作用机制 Refametinib is a non–ATP-competitive inhibitor of MEK1/2. X-ray revealed that refametinib binds to an allosteric site of MEK without affecting ATP binding but precluding binding to the substrate ERK, thus preventing ERK phosphorylation[3].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.75mL

0.35mL

0.17mL

8.74mL

1.75mL

0.87mL

17.47mL

3.49mL

1.75mL
参考文献

[1]Liu D, Xing J, Trink B, et al. BRAF mutation-selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR inhibitor temsirolimus. Int J Cancer. 2010 Dec 15;127(12):2965-73.

[2]Iverson C, Larson G, et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 2009 Sep 1;69(17):6839-47.

[3]Iverson C, Larson G, Lai C, Yeh LT, Dadson C, Weingarten P, Appleby T, Vo T, Maderna A, Vernier JM, Hamatake R, Miner JN, Quart B. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 2009 Sep 1;69(17):6839-47.

[4]Schmieder R, Puehler F, Neuhaus R, Kissel M, Adjei AA, Miner JN, Mumberg D, Ziegelbauer K, Scholz A. Allosteric MEK1/2 inhibitor refametinib (BAY 86-9766) in combination with sorafenib exhibits antitumor activity in preclinical murine and rat models of hepatocellular carcinoma. Neoplasia. 2013 Oct;15(10):1161-71.