Binimetinib, also known as Mektovi, is a potent and selective oral mitogen-activated protein kinase 1/2 (MEK 1/2) inhibitor with potential antineoplastic activity.
Binimetinib, noncompetitive with ATP, binds to and inhibits the activity of MEK1/2. Inhibition of MEK1/2 prevents the activation of MEK1/2 dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling. This may eventually lead to an inhibition of tumor cell proliferation and an inhibition in production of various inflammatory cytokines including interleukin-1, -6 and tumor necrosis factor.
Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cellfree 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.
The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib.
As shown in the co-crystal structure of
binimetinib in complex with BRAF–MEK1 kinases
and AMP–PNP (Fig. 1), the imine nitrogen of the
benzo[d]imidazole core hydrogen bonds to both the
amide NH of Ser212 and amide NH of Val211, and
the amide oxygen also forms a hydrogen bond with
the primary amine of Lys97. In addition, the terminal
hydroxyl group hydrogen bonds to the α-phosphate
oxygen of AMP–PNP. Also, the carboxamide side
chain oxygen interacts indirectly with the carboxylic
acid of Asp208 and AMP–PNP via a water molecule
(Fig. 2).
Binimetinib (606143-89-9) is a potent (IC50= 12 nM) and selective allosteric inhibitor of MEK1/2.1,2Recently approved by the FDA for treatment of melanoma in combination with Encorafenib. Binimetinib has had limited success as monotherapy but has shown promise in combination with other chemotherapeutic agents.3-5
MEK 162 is a MEK1/2 inhibitor allowing it to be a effective anti-cancer medication.
ChEBI: Binimetinib is a member of the class of benzimidazoles that is 1-methyl-1H-benzimidazole which is substituted at positions 4, 5, and 6 by fluorine, (4-bromo-2-fluorophenyl)nitrilo, and N-(2-hydroxyethoxy)aminocarbonyl groups, respectively. It is a MEK1 and MEK2 inhibitor (IC50= 12 nM). Approved by the FDA for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation in combination with encorafenib. It has a role as an EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor, an antineoplastic agent and an apoptosis inducer. It is a member of benzimidazoles, a member of bromobenzenes, a member of monofluorobenzenes, a hydroxamic acid ester and a secondary amino compound.
Class: dual threonine/tyrosine kinase;
Treatment: melanoma with BRAF mutations; Other name: ARRY-162; Oral bioavailability = 50%;
Elimination half-life = 3.5 h;
Protein binding = 97%
After oral administration, binimetinib is
absorbed rapidly, with a median tmax of 1.48 h.
Binimetinib is 50% orally bioavailable and exhibits a
short elimination half-life of 3.5 h. Consequently, it
requires twice-daily dosing regimen. Binimetinib undergoes UGT1A1-mediated
glucuronidation, which contributes up to 61% of the
overall metabolism. Other metabolic pathways
include N-dealkylation, amide hydrolysis, and loss of
ethanediol from the side chain.
[1] PATRICE A LEE. Abstract 2515: Preclinical Development of ARRY-162, A Potent and Selective MEK 1/2 Inhibitor[J]. Cancer research, 2010, 70 1: 2515-2515. DOI:
10.1158/1538-7445.am10-2515[2] S. WINSKI. 162 MEK162 (ARRY-162), a novel MEK 1/2 inhibitor, inhibits tumor growth regardless of KRas/Raf pathway mutations[J]. Ejc Supplements, 2010, 8 1: 56. DOI:
10.1016/s1359-6349(10)71867-x[3] MICHAEL S LEE. Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.[J]. Oncotarget, 2016: 39595-39608. DOI:
10.18632/oncotarget.9153[4] JUN GONG. MEK162 Enhances Antitumor Activity of 5-Fluorouracil and Trifluridine in KRAS-mutated Human Colorectal Cancer Cell Lines.[J]. Anticancer research, 2017, 37 6: 2831-2838. DOI:
10.21873/anticanres.11634[5] ERIC VAN CUTSEM. Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study.[J]. Journal of Clinical Oncology, 2019, 37 17: 1460-1469. DOI:
10.1200/jco.18.02459
