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.
PURPOSE: The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many humancancers 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.
Authors: John J Tentler; Sujatha Nallapareddy; Aik Choon Tan; Anna Spreafico; Todd M Pitts; M Pia Morelli; Heather M Selby; Maria I Kachaeva; Sara A Flanigan; Gillian N Kulikowski; Stephen Leong; John J Arcaroli; Wells A Messersmith; S Gail Eckhardt Journal: Mol Cancer Ther Date: 2010-10-05 Impact factor: 6.261
Authors: Edward B Garon; Richard S Finn; Wylie Hosmer; Judy Dering; Charles Ginther; Shahriar Adhami; Naeimeh Kamranpour; Sharon Pitts; Amrita Desai; David Elashoff; Tim French; Paul Smith; Dennis J Slamon Journal: Mol Cancer Ther Date: 2010-06-29 Impact factor: 6.261
Authors: Kazuhiko Shien; Vassiliki A Papadimitrakopoulou; Dennis Ruder; Carmen Behrens; Li Shen; Neda Kalhor; Juhee Song; J Jack Lee; Jing Wang; Ximing Tang; Roy S Herbst; Shinichi Toyooka; Luc Girard; John D Minna; Jonathan M Kurie; Ignacio I Wistuba; Julie G Izzo Journal: Mol Cancer Ther Date: 2017-07-20 Impact factor: 6.261
Authors: Chandra Bartholomeusz; Xuemei Xie; Mary Kathryn Pitner; Kimie Kondo; Ali Dadbin; Jangsoon Lee; Hitomi Saso; Paul D Smith; Kevin N Dalby; Naoto T Ueno Journal: Mol Cancer Ther Date: 2015-09-17 Impact factor: 6.261
Authors: Guangyao Kong; Mark Wunderlich; David Yang; Erik A Ranheim; Ken H Young; Jinyong Wang; Yuan-I Chang; Juan Du; Yangang Liu; Sin Ruow Tey; Xinmin Zhang; Mark Juckett; Ryan Mattison; Alisa Damnernsawad; Jingfang Zhang; James C Mulloy; Jing Zhang Journal: J Clin Invest Date: 2014-05-08 Impact factor: 14.808