RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer

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.

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

“…A similar targeted approach is being taken with the MEK-inhibitor refametinib (BAY 86-9766) in Ras-mutated HCC. Refametinib, a highly selective and potent small molecule allosteric (non-ATP-competitive) inhibitor of MEK 1 and MEK 2, showed potent single agent antitumor activity and acted synergistically in combination with sorafenib in preclinical HCC models, albeit with potential application for only a small subgroup of HCC patients [89][90][91] . Refa- …”

A Phase II Study of the Efficacy and Safety of the Combination Therapy of the MEK Inhibitor Refametinib (BAY 86-9766) Plus Sorafenib for Asian Patients with Unresectable Hepatocellular Carcinoma

“…The MAPK/ERK kinases 1 and 2 (MEK1 and 2) have been identified as potential oncology therapeutic targets (9). These enzymes are central components of the RAS signal transduction cascade, one of the main pathways activated in cancer that controls cellular proliferation, angiogenesis, apoptosis, and metastasis (10). Preclinical studies have demonstrated that overexpression of activated MAPK and MEK1 in HCC cell lines is associated with increased tumor growth and apoptotic resistance (11).…”

Multicenter Phase I Trial of the Mitogen-Activated Protein Kinase 1/2 Inhibitor BAY 86-9766 in Patients with Advanced Cancer

“…BAY 86-9766 (formerly RDEA119; VRX-621119) is a highly selective, potent, orally available, small-molecule allosteric (non-ATP-competitive) inhibitor of MEK1/2 (16). The drug binds to an allosteric site adjacent to the ATP-binding region and then interacts with ATP, the activation loop, and other surrounding residues to prevent binding of MEK to its substrate ERK, thereby blocking ERK phosphorylation (16).…”

“…The drug binds to an allosteric site adjacent to the ATP-binding region and then interacts with ATP, the activation loop, and other surrounding residues to prevent binding of MEK to its substrate ERK, thereby blocking ERK phosphorylation (16). BAY 86-9766 inhibited cell proliferation in human cancer cell lines, including those harboring BRAF V600E mutations, and also exhibited potent antitumor activity in xenograft models (16,17).…”