PDBsum entry 3e8n

Transferase

PDB id: 3e8n

Contents

Protein chain

291 a.a.

Ligands

ATP

VRA

Metals

_MG

Waters ×65

References listed in PDB file

Key reference

• Title: Rdea119/bay 869766: a potent, Selective, Allosteric inhibitor of mek1/2 for the treatment of cancer.
• Authors: C.Iverson, G.Larson, C.Lai, L.T.Yeh, C.Dadson, P.Weingarten, T.Appleby, T.Vo, A.Maderna, J.M.Vernier, R.Hamatake, J.N.Miner, B.Quart.
• Ref.: Cancer Res, 2009, 69, 6839-6847. [DOI no: 10.1158/0008-5472.CAN-09-0679]
• PubMed id: 19706763

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.