Binimetinib

Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents

Pharmaceuticals -> Listed in ZINC15

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; MEK Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

This chemical does not meet GHS hazard criteria for 92.5% (37 of 40) of all reports.

Not Classified

Aggregated GHS information provided per 40 reports by companies from 4 notifications to the ECHA C&L Inventory.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Binimetinib

Ambiguous-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models. MEK is an enzyme that regulates the biosynthesis of inflammatory cytokines such as TNF, IL-6 and IL-1; therefore, binimetinib anti-tumor activity can be mediated through the interference of cytokines biosynthesis. Binimetinib and [encorafenib] target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of [encorafenib] and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and [encorafenib] delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of [encorafenib] and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone. Following MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed.

Binimetinib, noncompetitive with ATP, binds reversibly to and inhibits the activity of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and 2. The inhibition of MEK1/2 prevents the activation of MEK1/2-dependent effector proteins and transcription factors, resulting in the inhibition of growth factor-mediated cell signaling such as the downstream extracellular signal-related kinase (ERK) pathway. This may lead to the inhibition of tumor cell proliferation and an inhibition in the production of various inflammatory cytokines including interleukin-1, -6, and tumor necrosis factor. MEK1/2 are themselves threonine and tyrosine kinases that possess a dual specificity. They subsequently contribute critically to the activation of the RAS/RAF/MEK/ERK pathway and are typically upregulated in a number of different tumor cell types.