| 词条 | Binimetinib |
| 释义 |
| drug_name = | IUPAC_name = 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzo[d]imidazole-6-carboxamide | image = Binimetinib.svg | alt = | caption = | tradename = | Drugs.com = | MedlinePlus = | pregnancy_AU = | pregnancy_US = | pregnancy_category= | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = Investigational | routes_of_administration = | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | CAS_number = 606143-89-9 | ATCvet = | ATC_prefix = L01 | ATC_suffix = XE41 | PubChem = 10288191 | ChEMBL = 3187723 | DrugBank =DB11967 | ChemSpiderID = 8463660 | KEGG = D10604 | C = 17 | H = 15 | Br = 1 | F = 2 | N = 4 | O = 3 | molecular_weight = 441.23 g/mol | smiles = CN1C=NC2=C1C=C(C(=C2F)NC3=C(C=C(C=C3)Br)F)C(=O)NOCCO | 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 |type=|licence_EU=|licence_US=}}Binimetinib, also known as Mektovi and ARRY-162, is an anti-cancer small molecule that was developed by Array Biopharma to treat various cancers.[1] Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway.[2] Inappropriate activation of the pathway has been shown to occur in many cancers.[2] 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.[3] Mechanism of actionBinimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, a MAP2K inhibitor.[4] MEK is part of the RAS pathway, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer.[5] 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.[6] 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.[7] 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.[8] 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.[8] DevelopmentIn 2015, it was in phase III clinical trials for ovarian cancer,[9] BRAF mutant melanoma,[10] and NRAS Q61 mutant melanoma.[11] In December 2015, the company announced that the mutant-NRAS melanoma trial was successful.[12] 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.[13] NDA submitted Jun 2016,[14] and the FDA should decide by 30 June 2017.[15] In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy.[16] Binimetinib was studied for treatment of rheumatoid arthritis, but a phase II trial did not show benefit. In 2017, the FDA informed Array Biopharma that the phase III trial data was not sufficient and the New Drug Application was withdrawn.[17] In June 2018 it was approved for the treatment of certain melanomas by the FDA in combination with encorafenib.[3] References1. ^{{cite web | publisher = Array Biopharma | title = Binimetinib | url = http://www.arraybiopharma.com/product-pipeline/binimetinib/ }} {{Extracellular chemotherapeutic agents}}2. ^1 {{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 }} 3. ^1 {{cite web | url = https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm611981.htm |title=Approved Drugs - FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations|last=Research|first=Center for Drug Evaluation and|website=www.fda.gov|language=en|access-date=2018-07-17}} 4. ^{{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 = 849–62 | date = December 2015 | pmid = 26615130 | pmc = 4663016 | doi = 10.1053/j.seminoncol.2015.09.023 }} 5. ^{{cite web | title = Binimetinib | url = https://pubchem.ncbi.nlm.nih.gov/compound/mek162 | work = PubChem }} 6. ^{{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 = 249–56 | date = March 2013 | pmid = 23414587 | doi = 10.1016/S1470-2045(13)70024-X }} 7. ^{{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 = 107–16 | date = February 2016 | pmid = 26767647 | doi = 10.1007/s11033-016-3943-9 }} 8. ^1 {{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 | pages = 172 | date = March 2016 | pmid = 26925841 | pmc = 4772351 | doi = 10.1186/s12885-016-2199-z }} 9. ^{{ClinicalTrialsGov|NCT01849874|A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer}} 10. ^{{ClinicalTrialsGov|NCT01909453|Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS)}} 11. ^{{ClinicalTrialsGov|NCT01763164|Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma}} 12. ^{{cite web | first = Austen | last = Hufford | name-list-format = vanc | url = https://www.wsj.com/articles/array-biopharma-has-successful-trial-for-cancer-drug-binimetinib-1450274949 | title = Array BioPharma Has Successful Trial for Cancer Drug Binimetinib | date = December 2015 | work = Wall Street Journal }} 13. ^{{cite web | url = http://www.metrodenver.org/news/news-center/2015/12/array-biopharma-announces-phase-3-binimetinib-trial-meets-primary-endpoint-for-nras-mutant-melanoma/ | title = Array BioPharma announces Phase 3 binimetinib trial meets primary endpoint for NRAS-mutant melanoma | work = Metro Denver | date = December 2015 }} 14. ^Array Bio submits marketing application in U.S. for lead product candidate in certain type of melanoma. June 2016 15. ^{{cite web | first = Douglas W. | last = House | name-list-format = vanc | url = http://seekingalpha.com/news/3206604-fda-accepts-array-bios-nda-binimetinib-action-date-june-30-shares-5-percent-premarket | title = FDA accepts Array Bio's NDA for binimetinib, action date June 30 | date = 1 September 2016 | work = Seeking Alpha }} 16. ^{{cite web | first = Douglas W. | last = House | name-list-format = vanc | url = http://seekingalpha.com/news/3170946-array-bags-phase-3-study-binimetinib-ovarian-cancer-shares-4-percent | title = Array bags Phase 3 study of binimetinib in ovarian cancer; shares down 4% | work = Seeking Alpha | date = 1 April 2016 }} 17. ^{{cite web | title = Losing Nemo: Array pulls skin cancer NDA for binimetinib| first = Ben | last = Adams | name-list-format = vanc | date = 20 March 2017 | work = Fierce Biotech | url = http://www.fiercebiotech.com/biotech/losing-nemo-array-pulls-skin-cancer-nda-for-binimetinib }} 5 : MEK inhibitors|cancer treatments|Benzamides|Fluoroarenes|Organobromides |
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