Purpose: 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. Experimental Design: 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.Excessive growth factor signaling leads to unregulated growth that can contribute to the pathogenesis of human cancer. The signaling cascade is initiated by the binding of peptide growth factors to their tyrosine kinase receptors at the plasma membrane. The receptor kinases are activated and through the recruitment of the growth factor receptor binding protein 2/son of sevenless complex to autophosphorylated sites on the receptors, the G protein Ras is induced to its active GTP-bound state. Ras recruits the serine/threonine kinase Raf to the plasma membrane, where it is then able to phosphorylate and activate mitogen-activated protein kinase kinases (MEK) 1 and 2, which are dual specificity protein kinases that phosphorylate serine/ threonine and tyrosine residues. The MEK kinases in turn phosphorylate and activate their only currently known substrates, extracellular signal-regulated kinases (ERK) 1 and 2. ERK1/2 proteins translocate to the nucleus where they phosphorylate and activate effector proteins and transcription factors, resulting in diverse cellular responses, including proliferation.The overexpression and/or mutation of epidermal growth factor (EGF) receptor (EGFR), erbB2, platelet-derived growth factor receptor, RET, and othe...

These data suggest that STHVH may be of major therapeutic value in the treatment of intractable cardiocirculatory failure complicating septic shock. Early initiation of therapy and adequate dose may improve hemodynamic and metabolic responses and 28-day survival.

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