Supplementary Data, Yeh, et al. from Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Yeh, Tammie C.; Marsh, Vivienne; Bernat, Bryan A.; Ballard, Josh; Colwell, Heidi; Evans, Ron J.; Parry, Janet; Smith, Darin; Brandhuber, Barbara J.; Gross, Stefan; Marlow, Allison; Hurley, Brian; Lyssikatos, Joe; Lee, Patrice A.; Winkler, James D.; Koch, Kevin; Wallace, Eli

doi:10.1158/1078-0432.22441213.v1

Supplementary Data, Yeh, et al. from Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

journal contribution

posted on 2023-03-31, 16:03 authored by Tammie C. Yeh, Vivienne Marsh, Bryan A. Bernat, Josh Ballard, Heidi Colwell, Ron J. Evans, Janet Parry, Darin Smith, Barbara J. Brandhuber, Stefan Gross, Allison Marlow, Brian Hurley, Joe Lyssikatos, Patrice A. Lee, James D. Winkler, Kevin Koch, Eli Wallace

Supplementary Data, Yeh, et al. from Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

History

ARTICLE ABSTRACT

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 IC50 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.