生物活性

• 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].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00785226	Advanced Cancer	Phase 1 Phase 2	Completed	-	United States, California ... more >> USC/Norris Comprehensive Cancer Center and LAC/USC Medical Center Los Angeles, California, United States, 90033 United States, Nevada Comprehensive Cancer Centers of Nevada Las Vegas, Nevada, United States, 89169 United States, New York New York Oncology Hematology, PC Albany, New York, United States, 12206 Roswell Park Cancer Institute Buffalo, New York, United States, 14263 James P. Wilmot Cancer Center Rochester, New York, United States, 14642 United States, Pennsylvania UPenn Philadelphia, Pennsylvania, United States, 19104 United States, South Carolina Greenville Hospital System University Medical Center, (ITOR) Greenville, South Carolina, United States, 29605 United States, Texas Texas Oncology - Baylor Charles A. Simmons Cancer Center Dallas, Texas, United States, 75246 Texas Oncology-Tyler Tyler, Texas, United States, 75702 Canada, Ontario Toronto General Hospital Toronto, Ontario, Canada, M5G 2N2 Collapse <<
  NCT01764828	Neoplasms	Phase 1	Completed	-	China ... more >> Shanghai, China, 200032 Japan Kashiwa, Chiba, Japan, 277-8577 Korea, Republic of Seoul, Korea, Republic of, 03080 Collapse <<
  NCT01392521	Neoplasms	Phase 1	Completed	-	United States, Arizona ... more >> Scottsdale, Arizona, United States, 85260 United States, Nevada Las Vegas, Nevada, United States, 89169 United States, South Carolina Greenville, South Carolina, United States, 29605 United States, Texas Houston, Texas, United States, 77030 Tyler, Texas, United States, 75702 United States, Washington Vancouver, Washington, United States, 98684 Germany Freiburg, Baden-Württemberg, Germany, 79106 Netherlands Rotterdam, Netherlands, 3015 CE Collapse <<

• 更多
• 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.