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
Binimetinib is a potent inhibitor of MEK1/2 with an IC50 of 12 nM in a cell-free assay.
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.
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%
Enzyme inhibitor
This MEK inhibitor (FW = 441.23 g/mol; CAS 606143-89-9; Solubility: 88
mg/mL DMSO, when warmed), also named MEK162, ARRY-162, ARRY-
438162, and 5- ( (4-bromo-2-fluorophenyl) amino) -4-fluoro-N- (2-hydroxy-
ethoxy) -1-methyl-1H-benzo[d]imidazole-6-carboxamide, targets Mitogen-
Activated Protein Kinase Kinase (MAPKK), also known as MAP2K and
MEK, which phosphorylates Mitogen-Activated Protein Kinase (MAPK).
(IC50 = 12 nM) and is the first targeted therapy to show activity in patients
with NRAS -mutated melanoma.
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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