Brain Distribution of a Novel MEK Inhibitor E6201: Implications in the Treatment of Melanoma Brain Metastases

Abstract

Clinically meaningful efficacy in the treatment of brain tumors, including melanoma brain metastases (MBM), requires selection of a potent inhibitor against a suitable target, and adequate drug distribution to target sites in the brain. Deregulated constitutive signaling of mitogen-activated protein kinase (MAPK) pathway has been frequently observed in melanoma, and mitogen-activated protein/extracellular signal-regulated kinase (MEK) has been identified to be an important target. E6201 is a potent synthetic small-molecule MEK inhibitor. The purpose of this study was to evaluate brain distribution of E6201, and examine the impact of active efflux transport at the blood-brain barrier on the central nervous system (CNS) exposure of E6201. In vitro studies utilizing transfected Madin-Darby canine kidney II (MDCKII) cells indicate that E6201 is not a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp). In vivo studies also suggest a minimal involvement of P-gp and Bcrp in E6201's brain distribution. The total concentrations in brain were higher than in plasma, resulting in a brain-to-plasma AUC ratio (Kp) of 2.66 in wild-type mice. The brain distribution was modestly enhanced in and knockout mice. The nonspecific binding of E6201 was higher in brain compared with plasma. However, free-drug concentrations in brain following 40 mg/kg intravenous dose reach levels that exceed reported in vitro half-maximal inhibitory concentration (IC) values, suggesting that E6201 may be efficacious in inhibiting MEK-driven brain tumors. The brain distribution characteristics of E6201 make it an attractive targeted agent for clinical testing in MBM, glioblastoma, and other CNS tumors that may be effectively targeted with inhibition of MEK signaling.

Profiling and Identification of Omeprazole Metabolites in Mouse Brain and Plasma by Isotope Ratio-Monitoring Liquid Chromatography-Mass Spectrometric Method

“…PK study results showed that omeprazole has a moderate clearance (37.75 ± 5.05 mL/min/kg) in mice. The brain-to-plasma coefficient (Kp) was calculated to evaluate the efficiency of omeprazole passing through the brain [22,23]. The ratios between area under the curve (AUC last ) values from brain and plasma were used for the calculation (Equation 1) and as a result, the Kp value was 0.15 for i.v.…”

Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities

“…If inferior pathway inhibition contributes to reduced response rates, there is the potential to overcome this through the use of higher doses of BRAFi + MEKi, a strategy which has been successfully used in the treatment of non‐small cell lung cancer brain metastases with EGFR mutations (Davies, ; How, Mann, Laczniak, & Baggstrom, ). Another strategy would be to develop and test BRAFi and/or MEKi with good blood–brain barrier or blood‐tumor penetration in the brain, such as the MEKi E6201, which is currently being studied in patients with BRAF‐mutant MBM (NCT03332589; Gampa et al, ). Alternatively, resistance could be caused by the activation of other signaling pathways in the tumor cells by the brain microenvironment, such as the aforementioned PI3K‐AKT and CDK4 pathways (Chen et al, ; Niessner et al, ).…”

Anti-tumor and anti-metastasis efficacy of E6201, a MEK1 inhibitor, in preclinical models of triple-negative breast cancer

“…E6201, a synthetic analog of a natural product, is an ATP-competitive dual kinase inhibitor of MEK1 and FLT3 [10,11]. Preclinical studies showed that E6201 may be useful for treatment of cancers associated with elevation of MEK1 kinase activity, including melanoma and acute myeloid leukemia [12][13][14][15]. E6201 has been evaluated in a phase I clinical trial in advanced solid tumors and melanoma (trial registration ID: NCT00794781).…”