Binimetinib Chemical Properties

Melting point:

>203oC (dec.)

Density 

1.67

storage temp. 

-20°C

solubility 

Soluble in DMSO (up to at least 25 mg/ml)

form 

solid

pka

14.20±0.10(Predicted)

color 

White

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.

Safety Information

HS Code 

2933998090

Binimetinib Usage And Synthesis

Kinase inhibitor

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.

Mechanism of Action

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.

Pharmacokinetics

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.

Binding Mode

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).

Description

Binimetinib (606143-89-9) is a potent (IC50?= 12 nM) and selective allosteric inhibitor of MEK1/2.1,2?Recently 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

Uses

MEK 162 is a MEK1/2 inhibitor allowing it to be a effective anti-cancer medication.

Definition

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.

brand name

Mektovi

General Description

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%

Pharmacokinetics

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.

target

Primary target: MEK1/2

References

1) Lee?et al.?(2010),?Preclinical development of ARRY-162, a potent and selective MEK1/2 inhibitor;?Cancer Res.?70?2515 2) Winski?et al.?(2010),?MEK162 (ARRY-162), a novel MEK ? inhibitor, inhibits tumor growth regardless of KRAS/RAF pathway mutations;?EJC Supplements?8?56 3) Lee?et al.?(2016),?Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models;?Oncotarget?7?39595 4) Gong?et al.?(2017),?MEK162 Enhances Antitumor Activity of 5-Fluorouracil and Trifluridine in KRAS-mutated Human Colorectal Cancer Cell Lines;?Anticancer Res.?37?2831 5) Van Cutsem?et al.?(2019),?Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From Phase III BEACON Colorectal Cancer study;?J. Clin. Oncol.?180?2459

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