Binimetinib, also known as Mektovi and ARRY-162, is an anti-cancer small molecule that was developed by

Array Biopharma Array BioPharma is an American clinical stage, pharmaceutical company that focuses on oncology medication headquartered in Boulder, Colorado. The company is a subsidiary of Pfizer. History In 1998, the company was founded by Drs. Tony Piscopio, K ...

to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

in the tumor-promoting

MAPK pathway A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...

. Inappropriate activation of the pathway has been shown to occur in many cancers. In June 2018 it was approved by the FDA in combination with

encorafenib Encorafenib, sold under the brand name Braftovi, is a medication for the treatment of certain melanoma cancers. It is a small molecule BRAF inhibitor that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different ...

for the treatment of patients with unresectable or metastatic BRAF

V600E V600E is a mutation of the BRAF gene in which valine (V) is substituted by glutamic acid (E) at amino acid 600. It is a driver mutation in a proportion of certain diagnoses, including melanoma, hairy cell leukemia, papillary thyroid carcinoma, ...

or V600K mutation-positive melanoma.

Mechanism of action

Binimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, a MAP2K inhibitor. MEK is part of the

RAS pathway Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals ...

, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer. 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. 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. 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. 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.

Development

In 2015, it was in phase III clinical trials for

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...

, BRAF mutant

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

, and NRAS Q61 mutant melanoma. In December 2015, the company announced that the mutant-NRAS melanoma trial was successful. 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.

NDA NDA may stand for: Military * National Defence Academy (India), a military academy in India * National Defence Act, legislation for organizing and funding Canada's military * National Defense Academy of Japan, a military academy in Japan * Nig ...

submitted Jun 2016, and the FDA should decide by 30 June 2017. In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy. Binimetinib was studied for treatment of

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

, 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. In June 2018, it was approved for the treatment of certain melanomas by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) in combination with encorafenib. 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. The trial was conducted at 162 sites in Europe, North America, and various countries around the world.

References

External links

* {{Portal bar, Medicine Benzamides Cancer treatments Fluoroarenes MEK inhibitors Bromoarenes Orphan drugs Pfizer brands