title: Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor.
abstract: OBJECTIVE
  The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many human cancers and is thus a target for novel therapeutics. We have developed a highly potent and selective inhibitor of MEK1/2. The purpose of these studies has been to show the biological efficacy of ARRY-142886 (AZD6244) in enzymatic, cellular, and animal models.
  
  
  METHODS
  The ability of ARRY-142886 to inhibit purified MEK1 as well as other kinases was evaluated. Its effects on extracellular signal-regulated kinase (ERK) phosphorylation and proliferation in several cell lines were also determined. Finally, the inhibitor was tested in HT-29 (colorectal) and BxPC3 (pancreatic) xenograft tumor models.
  
  
  RESULTS
  The IC(50) of ARRY-142886 was determined to be 14 nmol/L against purified MEK1. This activity is not competitive with ATP, which is consistent with the high specificity of compound for MEK1/2. Basal and epidermal growth factor-induced ERK1/2 phosphorylation was inhibited in several cell lines as well as 12-O-tetradecanoylphorbol-13-acetate-induced ERK1/2 phosphorylation in isolated peripheral blood mononuclear cells. Treatment with ARRY-142886 resulted in the growth inhibition of several cell lines containing B-Raf and Ras mutations but had no effect on a normal fibroblast cell line. When dosed orally, ARRY-142886 was capable of inhibiting both ERK1/2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions were also seen in a BxPC3 xenograft model. In addition, tumors remained responsive to growth inhibition after a 7-day dosing holiday.
  
  
  CONCLUSIONS
  ARRY-142886 is a potent and selective MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models. This compound is currently being investigated in clinical studies.
authors.affiliation: Array BioPharma, Inc., Boulder, Colorado 80301, USA. Tammie.Yeh@arraybiopharma.com
authors.forename: Tammie C
authors.initials: TC
authors.lastname: Yeh
authors.forename: Vivienne
authors.initials: V
authors.lastname: Marsh
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Bernat
authors.forename: Josh
authors.initials: J
authors.lastname: Ballard
authors.forename: Heidi
authors.initials: H
authors.lastname: Colwell
authors.forename: Ron J
authors.initials: RJ
authors.lastname: Evans
authors.forename: Janet
authors.initials: J
authors.lastname: Parry
authors.forename: Darin
authors.initials: D
authors.lastname: Smith
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brandhuber
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.forename: Allison
authors.initials: A
authors.lastname: Marlow
authors.forename: Brian
authors.initials: B
authors.lastname: Hurley
authors.forename: Joe
authors.initials: J
authors.lastname: Lyssikatos
authors.forename: Patrice A
authors.initials: PA
authors.lastname: Lee
authors.forename: James D
authors.initials: JD
authors.lastname: Winkler
authors.forename: Kevin
authors.initials: K
authors.lastname: Koch
authors.forename: Eli
authors.initials: E
authors.lastname: Wallace
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D048369:MAP Kinase Kinase 1 / Q000187:drug effects*; D048370:MAP Kinase Kinase 2 / Q000187:drug effects*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2