EasySep™小鼠TIL（CD45）正选试剂盒
产品号 #73372_C
MEK/ERK通路抑制剂；抑制MEK1和MEK2
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总览
Refametinib是丝裂原活化蛋白激酶激酶1（MEK1）和2（MEK2）的抑制剂，IC₅₀值分别为19 nM和47 nM。它与ATP口袋附近的变构位点结合，对MEK1/2和其他205种激酶具有选择性（Iverson 等）。
癌症研究
·体外抑制癌细胞系的生长，包括表达B-RAF突变V600E的细胞系（Iverson等）。
·抑制各种异种移植模型中的肿瘤生长，包括人黑色素瘤A375细胞系、人结肠癌Colo205细胞系以及原发性胰腺癌（Iverson等；Chang等）。
·与表皮生长因子受体（EGFR）抑制剂Erlotinib搭配使用，可协同诱导胰腺癌细胞系细胞凋亡（Diep等）。
·与酪氨酸激酶血管内皮生长因子受体（VEGFR）和血小板衍生生长因子受体（PDGFR）的抑制剂Sorafenib搭配使用，可协同抑制肝细胞癌啮齿动物模型中的肿瘤生长（Schmieder等）。
别名
BAY-86-9766；RDEA119
细胞类型
癌细胞及细胞系
种属
人，小鼠，非人灵长类，其它细胞系，大鼠
研究领域
癌症
CAS 编号
923032-37-5
化学式
C₁₉H₂₀F₃IN₂O₅S
分子量
572.3 克/摩尔
纯度
≥ 95 %
通路
MEK/ERK
靶点
MEK
产品说明书及文档
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相关材料与文献
技术资料 (2)
文献 (4)
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
Abstract
OBJECTIVE: The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK) inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC) models with different underlying etiologies in two species. DESIGN: Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA) were analyzed. RESULTS: BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK). BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo. CONCLUSION: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC.
Synergistic effect between erlotinib and MEK inhibitors in KRAS wild-type human pancreatic cancer cells. Clinical cancer research : an official journal of the American Association for Cancer Research 2011
Abstract
PURPOSE: The combination of erlotinib and gemcitabine has shown a small but statistically significant survival advantage when compared with gemcitabine alone in patients with advanced pancreatic cancer. However, the overall survival rate with the erlotinib and gemcitabine combination is still low. In this study, we sought to identify gene targets that, when inhibited, would enhance the activity of epidermal growth factor receptor (EGFR)-targeted therapies in pancreatic cancer cells. EXPERIMENTAL DESIGN: A high-throughput RNA interference (RNAi) screen was carried out to identify candidate genes. Selected gene hits were further confirmed and mechanisms of action were further investigated using various assays. RESULTS: Six gene hits from siRNA screening were confirmed to significantly sensitize BxPC-3 pancreatic cancer cells to erlotinib. One of the hits, mitogen-activated protein kinase (MAPK) 1, was selected for further mechanistic studies. Combination treatments of erlotinib and two MAP kinase kinase (MEK) inhibitors, RDEA119 and AZD6244, showed significant synergistic effect for both combinations (RDEA119-erlotinib and AZD6244-erlotinib) compared with the corresponding single drug treatments in pancreatic cancer cell lines with wild-type KRAS (BxPC-3 and Hs 700T) but not in cell lines with mutant KRAS (MIA PaCa-2 and PANC-1). The enhanced antitumor activity of the combination treatment was further verified in the BxPC-3 and MIA PaCa-2 mouse xenograft model. Examination of the MAPK signaling pathway by Western blotting indicated effective inhibition of the EGFR signaling by the drug combination in KRAS wild-type cells but not in KRAS mutant cells. CONCLUSIONS: Overall, our results suggest that combination therapy of an EGFR and MEK inhibitors may have enhanced efficacy in patients with pancreatic cancer.
Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts. BMC cancer 2010
Abstract
BACKGROUND: Combining MEK inhibitors with other signalling pathway inhibitors or conventional cytotoxic drugs represents a promising new strategy against cancer. RDEA119/BAY 869766 is a highly potent and selective MEK1/2 inhibitor undergoing phase I human clinical trials. The effects of RDEA119/BAY 869766 as a single agent and in combination with rapamycin were studied in 3 early passage primary pancreatic cancer xenografts, OCIP19, 21, and 23, grown orthotopically. METHODS: Anti-cancer effects were determined in separate groups following chronic drug exposure. Effects on cell cycle and downstream signalling were examined by flow cytometry and western blot, respectively. Plasma RDEA119 concentrations were measured to monitor the drug accumulation in vivo. RESULTS: RDEA119/BAY 869766 alone or in combination with rapamycin showed significant growth inhibition in all the 3 models, with a significant decrease in the percentage of cells in S-phase, accompanied by a large decrease in bromodeoxyuridine labelling and cell cycle arrest predominantly in G1. The S6 ribosomal protein was inhibited to a greater extent with combination treatment in all the three models. Blood plasma pharmacokinetic analyses indicated that RDEA119 levels achieved in vivo are similar to those that produce target inhibition and cell cycle arrest in vitro. CONCLUSIONS: Agents targeting the ERK and mTOR pathway have anticancer activity in primary xenografts, and these results support testing this combination in pancreatic cancer patients.
更多信息
| Molecular Weight | 572.3 g/mol |
|---|---|
| 种属 | Human, Mouse, Non-Human Primate, Other, Rat |
| Alternative Names | BAY-86-9766; RDEA119 |
| Cas Number | 923032-37-5 |
| Chemical Formula | C₁₉H₂₀F₃IN₂O₅S |
| 纯度 | ≥ 95% |
| Target | MEK |
| Pathway | MEK/ERK |
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