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Binimetinib

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Binimetinib
Clinical data
ATC code
Legal status
Legal status
  • Investigational
Identifiers
  • 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzo[d]imidazole-6-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.167.617 Edit this at Wikidata
Chemical and physical data
FormulaC17H15BrF2N4O3
Molar mass441.23 g/mol g·mol−1
3D model (JSmol)
  • CN1C=NC2=C1C=C(C(=C2F)NC3=C(C=C(C=C3)Br)F)C(=O)NOCCO
  • InChI=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)
  • Key:ACWZRVQXLIRSDF-UHFFFAOYSA-N

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 action

Binimetinib 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]

Development

In 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]

References

  1. ^ "Binimetinib". Array Biopharma.
  2. ^ a b Koelblinger P, Dornbierer J, Dummer R (August 2017). "A review of binimetinib for the treatment of mutant cutaneous melanoma". Future Oncology. 13 (20): 1755–1766. doi:10.2217/fon-2017-0170. PMID 28587477.
  3. ^ a b Research, Center for Drug Evaluation and. "Approved Drugs - FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations". www.fda.gov. Retrieved 2018-07-17.
  4. ^ Wu PK, Park JI (December 2015). "MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms". Seminars in Oncology. 42 (6): 849–62. doi:10.1053/j.seminoncol.2015.09.023. PMC 4663016. PMID 26615130.
  5. ^ "Binimetinib". PubChem.
  6. ^ 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 (March 2013). "MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study". The Lancet. Oncology. 14 (3): 249–56. doi:10.1016/S1470-2045(13)70024-X. PMID 23414587.
  7. ^ Mehdizadeh A, Somi MH, Darabi M, Jabbarpour-Bonyadi M (February 2016). "Extracellular signal-regulated kinase 1 and 2 in cancer therapy: a focus on hepatocellular carcinoma". Molecular Biology Reports. 43 (2): 107–16. doi:10.1007/s11033-016-3943-9. PMID 26767647.
  8. ^ a b Woodfield SE, Zhang L, Scorsone KA, Liu Y, Zage PE (March 2016). "Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression". BMC Cancer. 16: 172. doi:10.1186/s12885-016-2199-z. PMC 4772351. PMID 26925841.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ^ Clinical trial number NCT01849874 for "A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer" at ClinicalTrials.gov
  10. ^ Clinical trial number NCT01909453 for "Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS)" at ClinicalTrials.gov
  11. ^ Clinical trial number NCT01763164 for "Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma" at ClinicalTrials.gov
  12. ^ Hufford, Austen (December 2015). "Array BioPharma Has Successful Trial for Cancer Drug Binimetinib". Wall Street Journal. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  13. ^ "Array BioPharma announces Phase 3 binimetinib trial meets primary endpoint for NRAS-mutant melanoma". Metro Denver. December 2015.
  14. ^ Array Bio submits marketing application in U.S. for lead product candidate in certain type of melanoma. June 2016
  15. ^ House, Douglas W. (1 September 2016). "FDA accepts Array Bio's NDA for binimetinib, action date June 30". Seeking Alpha. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  16. ^ House, Douglas W. (1 April 2016). "Array bags Phase 3 study of binimetinib in ovarian cancer; shares down 4%". Seeking Alpha. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  17. ^ Adams, Ben (20 March 2017). "Losing Nemo: Array pulls skin cancer NDA for binimetinib". Fierce Biotech. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
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