Binimetinib

Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers.[5] Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway.[6] Inappropriate activation of the pathway has been shown to occur in many cancers.[6] In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.[7][8] In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib.[9] It was developed by Array Biopharma and Pfizer.

Mechanism of action

Binimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, a MAP2K inhibitor.[10] MEK is part of the RAS pathway, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer.[11] Binimetinib, uncompetitive with ATP, binds to and inhibits the activity of MEK1/2 kinase, which has been shown to regulate several key cellular activities including proliferation, survival, and angiogenesis.[12] MEK1/2 are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.[13] 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.[14] As demonstrated in preclinical studies, this may eventually lead to an inhibition of tumor cell proliferation and an inhibition in production of various inflammatory cytokines including

Development

In 2015, it was in phase III clinical trials for ovarian cancer,[15] BRAF mutant melanoma,[16] and NRAS Q61 mutant melanoma.[17]

In December 2015, the company announced that the mutant-NRAS melanoma trial was successful.[18] In the trial, those receiving binimetinib had a median progression-free survival of 2.8 months versus 1.5 months for those on the standard dacarbazine treatment.[19] NDA submitted Jun 2016,[20]

Synthesis

The synthesis of Binimetinib was recently reported:[25] The reaction of 2,3,4-trifluoro-5-nitrobenzoic acid [197520-71-1] (1) with O-(2-tert-butoxyethyl)hydroxylamine [1023742-13-3] (2) was achieved using CDI coupling agent and diisopropylethylamine to give 2,3,4-trifluoro-N-[2-[(2-methylpropan-2-yl)oxy]ethoxy]-5-nitrobenzamide, PC141452301 (3). Both of the activated fluorine atoms were displaced using ammonium hydroxide requiring the pressurized conditions of a steel bomb to furnish 2,4-diamino-3-fluoro-N-[2-[(2-methylpropan-2-yl)oxy]ethoxy]-5-nitrobenzamide, PC141452304 (4). Formation of the benzimidazole with formic acid with a catalytic amount of palladium hydroxide on carbon gave PC141452305 (5). The selective arylation with 4-bromo-2-fluoro-1-iodobenzene [105931-73-5] (6) in the presence of a highly specialized Pd2(dba)3 Xantphos catalyst exclusively yielded the hindered primary aniline, PC141452303 (7). The methylation of the benzimidazole secondary nitrogen with methyl iodide in the presence of potassium carbonate occurred chemoselectively. Treatment with an excess of aqueous phosphoric acid cleaved the terminal t-butyl ether completing the synthesis of binimetinib (8).

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