606143-89-9

Basic information

• Product Name: Binimetinib
• Synonyms: 5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide;ARRY-438162;MEK162;ARRY 162;ARRY-162;MEK162 (ARRY-438162);MEK162 (ARRY-162, ARRY-438162);BiniMetinib (MEK162, ARRY-162, ARRY-438162)
• CAS NO: 606143-89-9
• Molecular Formula: C₁₇H₁₅BrF₂N₄O₃
• Molecular Weight: 441.2268064
• Product Categories: API;Inhibitors;MAPK
• Mol File: 606143-89-9.mol
• Article Data: 6

Chemical Properties

• Appearance: /
• Density: 1.67
• Storage Temp.: -20°C
• Solubility: Soluble in DMSO (up to at least 25 mg/ml)
• PKA: 14.20±0.10(Predicted)
• 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.
• CAS DataBase Reference: Binimetinib(CAS DataBase Reference)
• NIST Chemistry Reference: Binimetinib(606143-89-9)
• EPA Substance Registry System: Binimetinib(606143-89-9)

Safety Data

• Hazardous Substances Data: 606143-89-9(Hazardous Substances Data)

Usage

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.

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.

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

Upstream product

• 606143-94-6 4-amino-3-fluoro-2-(2-fluoro-phenylamino)-5-nitro-benzoic acid methyl ester 
• 348-54-9 2-Fluoroaniline 
• 284030-58-6 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 
• 1604812-72-7 C₁₅H₉BrF₂N₃O₂^(1-)*K⁽¹⁺⁾ 
• 105931-73-5 1-bromo-3-fluoro-4-iodobenzene 
• 918321-20-7 methyl 5-amino-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate 
• 1604812-73-8 C₁₈H₁₂BrF₂N₅O 
• 1604812-70-5 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)amide 
• 1415564-99-6 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid 
• 1415559-93-1 methyl 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate 
• 606143-48-0 6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 

Relevant articles and documents

FORMS OF BINIMETINIB AND PROCESS FOR PREPARATION THEREOF

Amorphous forms of Binimetinib and processes for the preparation thereof.

PREPARATION OF AND FORMULATION COMPRISING A MEK INHIBITOR

The present invention relates to processes for preparing 6-(4-bromo-2- fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2- hydroxyethyoxy)-amide, processes for preparing crystallized 6-(4-bromo-2- fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2- hydroxyethyoxy)-amide, and intermediates useful therefore. Also provided herein are pharmaceutical compositions comprising this crystallized compound.

N3 ALKYLATED BENZIMIDAZOLE DERIVATIVES AS MEK INHIBITORS

-