Allosteric MEK1/2 Inhibitors for the Treatment of Cancer: an Overview

The RAS-RAF-MEK-ERK mitogen activated protein kinase (MAPK) pathway is a driver behind key cellular processes such as gene transcription, cellular proliferation, survival and motility and is aberrantly activated/dysregulated in many cancers.Mutations in RAS or RAF and/or increased signaling by receptor tyrosine kinases (RTK) associated with the cascade are frequently observed in many tumor settings and are linked to the dysregulation and aberrant activation of this pathway.MEK is a central component of this highly important cascade and has a unique allosteric pocket adjacent to its ATP binding site.As such, there has been an intense pursuit of allosteric small molecule inhibitors of this kinase.This pursuit, to date, has resulted in the advancement of 16 compounds to clinical trials and the approval of trametinib (Mekinist ® ) for the treatment of melanoma.In this brief review we provide an overview of the RAF-RAS-MEK-ERK cascade, its cancer implications and brief account of the allosteric MEK inhibitors that reached the clinic.