3E8N

X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) complexed with a potent inhibitor RDEA119 and MgATP

Summary for 3E8N

• Entry DOI: 10.2210/pdb3e8n/pdb
• Descriptor: Dual specificity mitogen-activated protein kinase kinase 1, MAGNESIUM ION, ADENOSINE-5'-TRIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: protein kinase-ligand-mgatp complex, rdea119, rdea-119, mek1, mek1-rdea119 complex, acetylation, atp-binding, disease mutation, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase, tyrosine-protein kinase
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 39034.43

Authors

Yan, S.,Wang, Z.M. (deposition date: 2008-08-20, release date: 2009-09-01, Last modification date: 2023-08-30)

Primary citation

Iverson, C.,Larson, G.,Lai, C.,Yeh, L.T.,Dadson, C.,Weingarten, P.,Appleby, T.,Vo, T.,Maderna, A.,Vernier, J.M.,Hamatake, R.,Miner, J.N.,Quart, B.
RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer.
Cancer Res., 69:6839-6847, 2009

PubMed 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.

PubMed: 19706763
DOI: 10.1158/0008-5472.CAN-09-0679

Experimental method

X-RAY DIFFRACTION (2.5 Å)