Inhibiting MEK 1/2: The Preclinical Advancements of ARRY-162 in Cancer Therapy

The Ras/Raf/MEK/MAPK pathway plays a critical role in cell division and tumor progression. Abnormal activation can be triggered by various factors, such as mutations in Ras and B-raf genes or by external stimuli like growth factors and cytokines. These mutations are prevalent in several types of cancer, with Ras mutations detected in a significant percentage of colon, pancreatic, and lung cancers, and B-raf mutations in melanomas and thyroid cancers. MEK, a crucial kinase in this pathway, activates ERK1/2, making it a promising target for cancer therapy.

A new compound, ARRY-162, has been identified as an ATP-uncompetitive inhibitor of MEK 1/2. It shows high selectivity and potency against MEK, with no effect on other kinases up to a certain concentration. ARRY-162 effectively reduces ERK phosphorylation in various cancer cell lines and is particularly effective against certain cell lines with mutant B-Raf and Ras. In animal models, ARRY-162 has shown significant tumor growth inhibition and tumor regression in several types of cancer, including colon and pancreatic carcinomas.

The compound's mechanism of action is linked to reduced levels of phospho-ERK in tumor xenografts. ARRY-162 also exhibits favorable properties for development, such as suitable chemical characteristics, moderate clearance, and minimal drug interactions. Following successful preclinical studies, ARRY-162 has moved into clinical development as a potential cancer treatment.