Compound DescriptionOral, selective allosteric MAPK kinase (MEK) inhibitor
Areas of ResearchMelanoma, non-small cell lung cancer (NSCLC), ovarian cancer, and pancreatic cancer
Proposed Mechanism of ActionBinimetinib (MEK162, Arry-162) is an oral, selective allosteric MEK inhibitor.1 MEK1 and MEK2 play an important role in cancer cell proliferation, differentiation, apoptosis, and metastasis. Both MEK1 and MEK2 are key components of the Ras-Raf-MEK-extracellular regulated signal kinases (ERK) signaling pathway (or MAPK signaling pathway).2,3 Hyperactivation of this signaling pathway through K-Ras, B-Raf, and receptor tyrosine kinase mutations is closely associated with the development of human tumors, such as melanoma, pancreatic, CRC, lung, and thyroid cancers and increases the sensitivity of tumor cells to MEK inhibitors.3,4
Key Preclinical DataBinimetinib is a small molecule inhibitor of MEK1 and MEK2 that binds to a pocket adjacent to the adenosine triphosphate (ATP) binding pocket in the kinase domain and is not competitive with ATP.1 Binimetinib inhibits MEK1/MEK2 in cell lines, which results in reduced phosphorylation of the MEK1/MEK2 substrates, pERK1 and pERK2, and reduced expression of downstream target genes.1,4
Binimetinib inhibits proliferation in a large number of cancer cell lines, especially cell lines with B-Raf and N-Ras mutations, and to a lesser degree K-Ras, all of which are components of the Raf-MEK-ERK intracellular pathway.4
In xenograft models, MEK162 demonstrated activity in K-Ras and B-Raf mutant tumors in CRC, NSCLC, and pancreatic cancer.4
Clinical StatusBinimetinib is currently being studied in various advanced or metastatic solid tumors including malignant. Phase Ib studies are ongoing in patients with various solid tumors in patients harboring B-Raf/Ras dependent disease, and in combination with phosphatidylinositol 3-kinase (PI3K) inhibitor (BKM120).5,6,8 In malignant melanoma, the NEMO (NRAS Melanoma and MEK inhibitor study) and COLUMBUS (Combined encorafenib (LGX818) plus binimetinib) Phase III trials in patients with NRAS and BRAF mutant melanoma are actively recruiting (NCT01763164).
The information contained herein was last updated on April 12, 2013.
All Compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.
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