Selumetinib

Appearance: White to off-white solid. Solubility: Soluble in DMSO (100mg/ml). Soluble in ethanol (~1mg/ml with warming). Insoluble in water. InChi Key: CYOHGALHFOKKQC-UHFFFAOYSA-N Smiles: Cn1cnc2c1cc(c(c2F)Nc3ccc(cc3Cl)Br)C(=O)NOCCO Selumetinib is an orally available, potent and selective ATP non-competitive inhibitor of the mitogen-activated protein kinases MEK1 (IC50 = 14 nM) and MEK2 (Kd = 530 nM). MEK1 and MEK2 specifically act downstream of growth factor receptors and the proto-oncogenes Ras and Raf to activate ERK1 and ERK2, often leading to an increase in cell proliferation. It inhibits ERK1/2 phosphorylation (IC50 = 10 nM), but exhibits only weak activity at p38alpha, MKK6, EGFR, ErbB2 and ERK2. Selumetinib inhibits growth of several tumor cell lines but not normal fibroblast lines and shows potent dose-dependent antitumor activity against a panel of mouse xenograft models of colorectal, pancreatic, liver, skin and lung cancer. It inhibits proliferation and induces differentiation and apoptosis in multiple tumor cell lines and tumor xenograft models, and inhibits proliferation of breast cancer and non-small cell lung cancer cell lines, especially those containing Raf and Ras mutations, respectively. Product References Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor: T.C. Yeh, et al., Clin. Cancer. Res. 13, 1576 (2007) Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma: H. Huynh, et al., Mol. Cancer Ther. 6, 138 (2007) Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244: D.W. Ball, et al., J. Clin. Endocrinol. Metab. 92, 4712 (2007) AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models: B.R. Davies, et al., Mol. Cancer Ther. 6, 2209 (2007) Comprehensive analysis of kinase inhibitor selectivity: M.I. Davis, et al., Nat. Biotechnol. 29, 1046 (2011) The MEK1/2 inhibitor, selumetinib (AZD6244, ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models: S.V. Holt, et al., Br. J. Cancer 106, 858 (2012) Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories: I.V. Hartung, et al., Bioorg. Med. Chem. Lett. 23, 2384 (2013) Selumetinib in the treatment of non-small-cell lung cancer: R. Bernabe, et al., Future Oncol. 12, 2545 (2016) (Review) Treating non-small cell lung cancer with selumetinib: an up-to-date drug evaluation: E.N. Imyanitov, et al., Expert Opin. Pharmacother. 21, 1943 (2020) (Review) A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas: M.K. Anderson, et al., Ann. Pharmacother. 56, 716 (2022) (Review) Selumetinib: a selective MEK1 inhibitor for solid tumor treatment: M. Hedayat, et al., Clin. Exp. Med. (Epub ahead of Print) (2022) (Review)