Binimetinib

{{Short description|Chemical compound}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Use dmy dates|date=July 2024}}

{{Drugbox | image = Binimetinib.svg | image_class = skin-invert-image | alt = | caption = | type =

| tradename = Mektovi | Drugs.com = {{drugs.com|monograph|binimetinib}} | MedlinePlus = a618041 | DailyMedID = Binimetinib | pregnancy_AU = | pregnancy_category= | routes_of_administration = | class = Antineoplastic agent | ATC_prefix = L01 | ATC_suffix = EE03

| legal_AU = S4 | legal_AU_comment = <ref>{{cite web | title = Therapeutic Goods (Poisons Standard— June 2025) Instrument 2025 | date = May 2025 | website = Therapeutic Goods Administration (TGA) | url = https://www.legislation.gov.au/F2025L00599/asmade/2025-05-28/text/original/pdf | format = pdf | access-date = 31 August 2025 }}</ref> | legal_CA = Rx-only | legal_CA_comment =<ref>{{cite web | title = Product monograph | url = https://pdf.hres.ca/dpd_pm/00060288.PDF | website = hres.ca | access-date = 19 October 2023 | archive-date = 18 February 2024 | archive-url = https://web.archive.org/web/20240218073028/https://pdf.hres.ca/dpd_pm/00060288.PDF | url-status = live }}</ref><ref>{{cite web | title = Summary Basis of Decision (SBD) for Mektovi | date = 23 October 2014 | website = Health Canada | url = https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00533&lang=en | access-date = 29 May 2022 | archive-date = 30 May 2022 | archive-url = https://web.archive.org/web/20220530042005/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00533&lang=en | url-status = live }}</ref> | legal_UK =  | legal_US = Rx-only | legal_EU = Rx-only | legal_EU_comment = <ref>{{cite web | title = Mektovi EPAR | date = 20 September 2018 | website = European Medicines Agency | url = https://www.ema.europa.eu/en/medicines/human/EPAR/mektovi | access-date = 5 July 2024 | archive-date = 6 October 2021 | archive-url = https://web.archive.org/web/20211006130825/https://www.ema.europa.eu/en/medicines/human/EPAR/mektovi | url-status = live }}</ref> | legal_status =

| IUPAC_name = 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-''N''-(2-hydroxyethoxy)-1-methyl-1''H''-benzo[''d'']imidazole-6-carboxamide | C = 17 | H = 15 | Br = 1 | F = 2 | N = 4 | O = 3 | SMILES = Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NOCCO)cc21 | StdInChI = 1S/C17H15BrF2N4O3/c1-24-8-21-16-13(24)7-10(17(26)23-27-5-4-25)15(14(16)20)22-12-3-2-9(18)6-11(12)19/h2-3,6-8,22,25H,4-5H2,1H3,(H,23,26) | StdInChIKey = ACWZRVQXLIRSDF-UHFFFAOYSA-N }}

'''Binimetinib''', sold under the brand name '''Mektovi''', is an anti-cancer medication used to treat various cancers.<ref>{{cite web | title = Binimetinib | publisher = Array Biopharma | url = http://www.arraybiopharma.com/product-pipeline/binimetinib/ | access-date = 6 April 2015 | archive-date = 4 June 2019 | archive-url = https://web.archive.org/web/20190604043216/http://www.arraybiopharma.com/product-pipeline/binimetinib/ | url-status = live }}</ref> Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway.<ref name="Koelblinger_2017">{{cite journal | vauthors = Koelblinger P, Dornbierer J, Dummer R | title = A review of binimetinib for the treatment of mutant cutaneous melanoma | journal = Future Oncology | volume = 13 | issue = 20 | pages = 1755–1766 | date = August 2017 | pmid = 28587477 | doi = 10.2217/fon-2017-0170 | doi-access = free }}</ref> Inappropriate activation of the pathway has been shown to occur in many cancers.<ref name="Koelblinger_2017" /> 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.<ref name="FDA PR">{{cite press release | title = FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations | date = 27 June 2018 | publisher = U.S. Food and Drug Administration (FDA) | url = https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-and-binimetinib-combination-unresectable-or-metastatic-melanoma-braf | archive-url = https://web.archive.org/web/20191219041947/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-and-binimetinib-combination-unresectable-or-metastatic-melanoma-braf | archive-date = 19 December 2019 | url-status = live | access-date = 17 July 2018 }} {{PD-notice}}</ref><ref name="FDA Snapshot">{{cite web | title = Drug Trial Snapshot: Mektovi | date = 19 December 2019 | publisher = U.S. Food and Drug Administration (FDA) | url = https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-mektovi | archive-url = https://web.archive.org/web/20191219042036/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-mektovi | archive-date = 19 December 2019 | url-status = live | access-date = 19 December 2019 }} {{PD-notice}}</ref> In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib.<ref name=":1">{{cite web | title = FDA approves encorafenib with binimetinib for metastatic non-small cell lung cancer with a BRAF V600E mutation | date = 11 October 2023 | url = https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-binimetinib-metastatic-non-small-cell-lung-cancer-braf-v600e-mutation | access-date = 11 October 2023 | website = U.S. Food and Drug Administration }}</ref> 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.<ref>{{cite journal | vauthors = Wu PK, Park JI | title = MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms | journal = Seminars in Oncology | volume = 42 | issue = 6 | pages = 849–862 | date = December 2015 | pmid = 26615130 | pmc = 4663016 | doi = 10.1053/j.seminoncol.2015.09.023 }}</ref> MEK is part of the RAS pathway, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer.<ref>{{cite web | title = Binimetinib | url = https://pubchem.ncbi.nlm.nih.gov/compound/mek162 | work = PubChem | access-date = 26 January 2017 | archive-date = 6 January 2021 | archive-url = https://web.archive.org/web/20210106092525/https://pubchem.ncbi.nlm.nih.gov/compound/mek162 | url-status = live }}</ref> 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.<ref>{{cite journal | vauthors = Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, Blank CU, Hauschild A, Beck JT, St-Pierre A, Niazi F, Wandel S, Peters M, Zubel A, Dummer R | title = MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study | journal = The Lancet. Oncology | volume = 14 | issue = 3 | pages = 249–256 | date = March 2013 | pmid = 23414587 | doi = 10.1016/S1470-2045(13)70024-X }}</ref> 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.<ref name="Mehdizadeh_2016">{{cite journal | vauthors = Mehdizadeh A, Somi MH, Darabi M, Jabbarpour-Bonyadi M | title = Extracellular signal-regulated kinase 1 and 2 in cancer therapy: a focus on hepatocellular carcinoma | journal = Molecular Biology Reports | volume = 43 | issue = 2 | pages = 107–116 | date = February 2016 | pmid = 26767647 | doi = 10.1007/s11033-016-3943-9 | s2cid = 15113957 }}</ref> 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.<ref name="Woodfield_2016">{{cite journal | vauthors = Woodfield SE, Zhang L, Scorsone KA, Liu Y, Zage PE | title = Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression | journal = BMC Cancer | volume = 16 | date = March 2016 | pmid = 26925841 | pmc = 4772351 | doi = 10.1186/s12885-016-2199-z | doi-access = free | article-number = 172 }}</ref> 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 interleukin-1, -6 and tumor necrosis factor.<ref name="Woodfield_2016" />

== Development == In 2015, it was in phase III clinical trials for ovarian cancer,<ref>{{ClinicalTrialsGov|NCT01849874|A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer}}</ref> BRAF mutant melanoma,<ref>{{ClinicalTrialsGov|NCT01909453|Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS)}}</ref> and NRAS Q61 mutant melanoma.<ref name=NCT01763164>{{ClinicalTrialsGov|NCT01763164|Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma}}</ref>

In December 2015, the company announced that the mutant-NRAS melanoma trial was successful.<ref name="Hufford_2015">{{cite web | vauthors = Hufford A | title = Array BioPharma Has Successful Trial for Cancer Drug Binimetinib | date = December 2015 | url = https://www.wsj.com/articles/array-biopharma-has-successful-trial-for-cancer-drug-binimetinib-1450274949 | work = Wall Street Journal | access-date = 5 March 2017 | archive-date = 6 January 2021 | archive-url = https://web.archive.org/web/20210106144100/https://www.wsj.com/articles/array-biopharma-has-successful-trial-for-cancer-drug-binimetinib-1450274949 | url-status = live }}</ref> 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.<ref>{{cite web | title = Array BioPharma announces Phase 3 binimetinib trial meets primary endpoint for NRAS-mutant melanoma | date = December 2015 | url = http://www.metrodenver.org/news/news-center/2015/12/array-biopharma-announces-phase-3-binimetinib-trial-meets-primary-endpoint-for-nras-mutant-melanoma/ | work = Metro Denver | access-date = 14 March 2016 | archive-date = 7 January 2021 | archive-url = https://web.archive.org/web/20210107001850/http://www.metrodenver.org/news/news-center/2015/12/array-biopharma-announces-phase-3-binimetinib-trial-meets-primary-endpoint-for-nras-mutant-melanoma | url-status = dead }}</ref> NDA submitted Jun 2016,<ref>{{Cite web | title = Array Bio submits marketing application in U.S. for lead product candidate in certain type of melanoma. June 2016 | date = 30 June 2016 | url = http://seekingalpha.com/news/3191356-array-bio-submits-marketing-application-u-s-lead-product-candidate-certain-type-melanoma | access-date = 5 July 2016 | archive-date = 15 August 2016 | archive-url = https://web.archive.org/web/20160815061552/http://seekingalpha.com/news/3191356-array-bio-submits-marketing-application-u-s-lead-product-candidate-certain-type-melanoma | url-status = live }}</ref> and the FDA should decide by 30 June 2017.<ref>{{cite web | vauthors = House DW | title = FDA accepts Array Bio's NDA for binimetinib, action date June 30 | date = 1 September 2016 | url = http://seekingalpha.com/news/3206604-fda-accepts-array-bios-nda-binimetinib-action-date-june-30-shares-5-percent-premarket | work = Seeking Alpha | access-date = 6 September 2016 | archive-date = 19 September 2016 | archive-url = https://web.archive.org/web/20160919020200/http://seekingalpha.com/news/3206604-fda-accepts-array-bios-nda-binimetinib-action-date-june-30-shares-5-percent-premarket | url-status = live }}</ref>

In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy.<ref>{{cite web | vauthors = House DW | title = Array bags Phase 3 study of binimetinib in ovarian cancer; shares down 4% | date = 1 April 2016 | url = http://seekingalpha.com/news/3170946-array-bags-phase-3-study-binimetinib-ovarian-cancer-shares-4-percent | work = Seeking Alpha | access-date = 3 April 2016 | archive-date = 6 December 2016 | archive-url = https://web.archive.org/web/20161206080851/http://seekingalpha.com/news/3170946-array-bags-phase-3-study-binimetinib-ovarian-cancer-shares-4-percent | url-status = live }}</ref>

In 2017, the FDA informed Array Biopharma that the phase III trial data was not sufficient and the New Drug Application was withdrawn.<ref>{{cite web | vauthors = Adams B | title = Losing Nemo: Array pulls skin cancer NDA for binimetinib | date = 20 March 2017 | work = Fierce Biotech | url = http://www.fiercebiotech.com/biotech/losing-nemo-array-pulls-skin-cancer-nda-for-binimetinib | access-date = 2 May 2017 | archive-date = 6 January 2021 | archive-url = https://web.archive.org/web/20210106145144/https://www.fiercebiotech.com/biotech/losing-nemo-array-pulls-skin-cancer-nda-for-binimetinib | url-status = live }}</ref>

In June 2018, it was approved for the treatment of certain melanomas by the U.S. Food and Drug Administration (FDA) in combination with encorafenib.<ref name="FDA PR" /> The FDA approved binimetinib based primarily on evidence from one clinical trial (NCT01909453) of 383 patients with BRAF V600 mutation-positive melanoma that was advanced or could not be removed by surgery.<ref name="FDA Snapshot" /> The trial was conducted at 162 sites in Europe, North America, and various countries around the world.<ref name="FDA Snapshot" />

In October 2023, the US Food and Drug Administration approved encorafenib with binimetinib for adults with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test based on the results of the PHAROS trial. <ref>{{cite journal | vauthors = Riely GJ, Smit EF, Ahn MJ, Felip E, Ramalingam SS, Tsao A, Johnson M, Gelsomino F, Esper R, Nadal E, Offin M, Provencio M, Clarke J, Hussain M, Otterson GA, Dagogo-Jack I, Goldman JW, Morgensztern D, Alcasid A, Usari T, Wissel P, Wilner K, Pathan N, Tonkovyd S, Johnson BE | title = Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With ''BRAF''<sup>V600</sup>-Mutant Metastatic Non-Small-Cell Lung Cancer | journal = Journal of Clinical Oncology | volume = 41 | issue = 21 | pages = 3700–3711 | date = July 2023 | pmid = 37270692 | doi = 10.1200/JCO.23.00774 }}</ref><ref name=":1" /> ==Synthesis== The synthesis of Binimetinib was recently reported:<ref>{{cite journal | vauthors = Flick AC, Leverett CA, Ding HX, McInturff E, Fink SJ, Helal CJ, DeForest JC, Morse PD, Mahapatra S, O'Donnell CJ | title = Synthetic Approaches to New Drugs Approved during 2018 | journal = Journal of Medicinal Chemistry | volume = 63 | issue = 19 | pages = 10652–10704 | date = October 2020 | pmid = 32338902 | doi = 10.1021/acs.jmedchem.0c00345 }}</ref> class=skin-invert-image|700px|center 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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Category:Benzamides Category:Cancer treatments Category:Fluorobenzene derivatives Category:MEK inhibitors Category:Bromobenzene derivatives Category:Orphan drugs Category:Drugs developed by Pfizer Category:Hydroxyethyl compounds