Abstract
The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncology therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The structural, pharmacologic, and pharmacokinetic properties of RDEA119/BAY 869766, an allosteric MEK inhibitor, are presented. RDEA119/BAY 869766 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes. This compound is highly efficacious at inhibiting cell proliferation in several tumor cell lines in vitro. In vivo, RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system-related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, RDEA119/BAY 869766 has the potential for use as a once- or twice-daily oral treatment for cancer. RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clinical development because of its potency and favorable pharmacokinetic profile.
Highlights
Cancer is the second most common cause of death in the United States
The RDEA119-MEK complex structure reveals that RDEA119 binds to an allosteric site adjacent to the Mg-ATP binding region and interacts extensively with ATP, the activation loop, and other surrounding protein residues through hydrogen bonding and hydrophobic interactions (Fig. 1B and C)
Such selectivity is achieved by the interaction of the inhibitor with a hydrophobic pocket in MEK that interferes with subsequent binding and hydrolysis of ATP [10]
Summary
Cancer is the second most common cause of death in the United States (one of four deaths; ref. 1). Cancer is the second most common cause of death in the United States Progress is being made, as measured by an increase in the 5-year survival rate from f50% in the 1970s to 66% for people diagnosed with cancer between 1996 and 2002, there is still significant unmet medical need among patients with cancer [1, 2]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Maderna: Wyeth Research, Chemical Sciences, 401 North Middletown Road, Pearl River, NY 10965. Hamatake: Glaxo SmithKline, 5 Moore Drive, Research Triangle Park, NC 27709. Appleby: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404. Weingarten: Abraxis Research, 4503 Glencoe Avenue, Marina del Rey, CA 90292
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