368 Demonstration of broad in vivo anti-tumor activity of ARRY-142886 (AZD-6244), a potent and selective MEK inhibitor

Lee, P.A.; Wallace, E.; Yeh, Tammie C.; Pöch, G; Hunt, D. E.; Pheneger, Tracy; Woessner, Richard; Cartlidge, S.; Klinowska, Teresa; Winkler, Jim

doi:10.1016/s1359-6349(04)80375-6

Cited by 5 publications

(5 citation statements)

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“…Efficacy has been shown with ARRY-142886 in other human xenograft models, including MIA PaCa-2, HCT-116, LOX, Calu6, and A549 (34,36). Notably, tumor regressions were seen in models for pancreatic cancer and melanoma, cancer types where activating mutations of the MEK pathway have been identified.…”

Section: Discussionmentioning

confidence: 97%

Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Yeh

Marsh²,

Bernat³

et al. 2007

Clinical Cancer Research

510

376

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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...

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Section: Discussionmentioning

confidence: 97%

Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Yeh

Marsh²,

Bernat³

et al. 2007

Clinical Cancer Research

510

376

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“…AZD6244 is an oral, non-ATP competitive inhibitor and highly specific for MEK1/2, a key enzyme in the Ras-Raf-MEK-ERK pathway. AZD6244 had minimal effects on the p38, c-Jun-NH 2 -kinase, phosphatidylinositol 3-kinase, and MEK5/ERK5 pathways (28). AZD6244 inhibits both basal and induced levels of ERK1/2 phosphorylation in numerous cancer cell lines with an IC 50 as low as 8 nmol/L.…”

Section: Introductionmentioning

confidence: 95%

“…It has also shown efficacy in numerous tumor models (29). Sustained inhibition of ERK activity in tumors can be achieved at a dose of 10 mg/kg/d in xenograft studies in mice (28). AZD6244 is currently in phase I clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma

Huynh

Soo

Chow

et al. 2007

Molecular Cancer Therapeutics

140

107

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Hepatocellular carcinoma (HCC) is a common malignancy in Asia and Africa. We previously reported that overexpression of extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2) and ERK1/2 was detected in HCC, and that their activation was required for liver cancer cell proliferation and survival. In the present study, we determined the efficacy of a specific MEK1/2 inhibitor AZD6244 (ARRAY-142886) in treatment of HCC. Treatment of primary HCC cells with AZD6244 led to growth inhibition, elevation of the cleavage of caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase, but inhibition of ERK1/2 and p90RSK phosphorylation. Studying the protein expression profile of seven HCC xenografts revealed that their growth rate was positively correlated with the levels of phosphorylated MEK. AZD6244, when given p.o. to mice bearing these xenografts, resulted in a dose-dependent inhibition of tumor growth. AZD6244-induced growth suppression was associated with inactivation of ERK1/2 and p90RSK, and up-regulation of activated caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase. Our data suggest that the MEK-ERK pathway plays an important role in the growth and survival of liver cancer cells and that the HCC xenograft models are excellent tools for screening preclinical drugs.

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“…• small molecule inhibitors of RAF (BAY 43-9006 (1)) [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. • small molecule inhibitors of MEK (PD-0325901 (5) and ARRY-142886 (6)) [54][55][56][57][58].…”

Section: The Erk Pathway As a Target For Cancer Drug Discoverymentioning

confidence: 99%

“…Two small-molecule MEK inhibitors are currently being evaluated in the clinic, PD-0325901 (5, Pfizer) [54][55][56] and ARRY-142886 (6, AZD-6244, Array and AstraZeneca) [57,58]. These two agents, which are orally bioavailable, are both non-ATP competitive allosteric inhibitors of MEK.…”

Section: The Erk Pathway As a Target For Cancer Drug Discoverymentioning

confidence: 99%

Recent Advances in the Research and Development of RAF Kinase Inhibitors

Smith¹,

Dumas²,

Adnane³

et al. 2006

CTMC

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The RAS-RAF-MEK-ERK signaling pathway (ERK pathway) plays a key role in tumorigenesis and cancer progression. Mutations of RAS or B-RAF lead to a constitutive activation of the ERK pathway, which ultimately results in increased cell division, and cell survival. This review article focuses on the recent literature related to ERK pathway inhibitors, with a particular emphasis on RAF kinase inhibitors. Preclinical and clinical data for the RAF kinase inhibitor sorafenib (BAY 43-9006 tosylate), that was recently approved in the US for the treatment of advanced renal cell carcinoma, are also outlined.

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368 Demonstration of broad in vivo anti-tumor activity of ARRY-142886 (AZD-6244), a potent and selective MEK inhibitor

Cited by 5 publications

References 0 publications

Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma

Recent Advances in the Research and Development of RAF Kinase Inhibitors

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