生物活性

• 靶点

  ERK1 IC50:10nM

  ERK2 IC50:10nM

  MEK1 IC50:14nM

• 描述The Ras-Raf-MEK pathway is overactive in many human cancers, such as melanoma and NSCLC. Selumetinib, also called as ARRY-142886 or AZD6244, is a potent and highly selective MEK1/2 inhibitor with IC50 of 14 nM (measured by the catalytic activation of purified His-MEK1 on ERK2). Selumetinib can inhibit the enzymatic activity of MEK1/2 but not the MEK1/2 phosphorylation by Raf. IC50 of Selumetinib to inhibit MEK1/2 phosphorylation on ERK1/2 in cell lines examed is less than 40 nM. In EGFR-overexpressed A431 cells, EGF-induced ERK1/2 phosphorylation can be inhibited by Selumetinib at the concentration < 10 μM in a dose-dependent manner, while no obvious inhibition can be observed in ERK5. In cell growth study, Selumetinib shows more potent in cell lines containing activating B-Raf and Ras mutations (HT-29, Malme-3M, MIA PaCa-2, SK-MEL-2, SK-MEL-28 cells, IC50 values ranging from 59 to 473 nM), while it had no effect on other cell lines examined, including BxPC3, BT474 and Malme-3 cells with no Raf/Ras-mutantion reported. 21-day administration of selumetinib orally, BID, can inhibit the tumour growth up to 70% at the concentration of 100 mg/kg in mice bearing HT-29 tumors and inhibition of phospho-ERK1/2 was seen^[1]. Selumetinib is mainly used in the study of melanoma, NSCLC, Neurofibromatosis type 1 etc.^[2].
• 作用机制Molecular modeling data shows Selumetinib can bind to the allosteric inhibitor binding site in MEK1/2^[1].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human A101D cell	-	Growth inhibition assay	-	Inhibition of human A101D cell growth in a cell viability assay, IC50=240.33 nM.	SANGER
  human A375 cells	-	Proliferation assay	72 h	Antiproliferative activity against human A375 cells expressing BRAF V600E mutant after 72 hrs by Cell titer-glo assay, IC50=31 nM.	23474388
  human A549 cell	-	Growth inhibition assay	-	Inhibition of human A549 cell growth in a cell viability assay, IC50=214.13 nM.	SANGER

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• 动物研究
  剂量	Mice[3] (i.p.): min = 25 mg/kg, max = 100 mg/kg
  给药途径	i.p.
  动物药代数据	Animal Nude mice[4] Dose 10 mg/kg Administration p.o. Cmax 2977 ng/ml T1/2 2.29 h Tmax 1.0 h AUC 17525 ng/(ml·h) Vz/F 1.9 L/kg Cl/F 0.6 L/(h·kg)

• 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
  NCT00085787	Advanced Cancer	Phase 1	Completed	-	United States, Colorado ... more >> University of Colorado Cancer Center, Anschutz Cancer Center Aurora, Colorado, United States, 80010 United States, Minnesota Mayo Clinic Rochester Rochester, Minnesota, United States, 55905 United States, Pennsylvania Fox Chase Cancer Center Philadelphia, Pennsylvania, United States, 19111 Collapse <<
  NCT00780676	Breast Cancer	Phase 2	Terminated(Closed early for fu... more >>tility.) Collapse <<	-	United States, Texas ... more >> UT MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT02546661	Muscle Invasive Bladder Cancer	Phase 1	Recruiting	March 27, 2020	-

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• 参考文献

• [1] Yeh TC, Marsh V, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007 Mar 1;13(5):1576-83.

  [2] Bernabé R, Patrao A, et al. Selumetinib in the treatment of non-small-cell lung cancer. Future Oncol. 2016 Nov;12(22):2545-2560.

  [3] Bartholomeusz C, Oishi T, et al. MEK1/2 inhibitor selumetinib (AZD6244) inhibits growth of ovarian clear cell carcinoma in a PEA-15-dependent manner in a mouse xenograft model. Mol Cancer Ther. 2012 Feb;11(2):360-9.

  [4] Denton CL, Gustafson DL, et al. Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice. Cancer Chemother Pharmacol. 2011 Feb;67(2):349-60.