RAS/RAF/MEK Inhibitors in Oncology

M.      Broggini

doi:10.2174/092986712799320510

Abstract

The RAS/RAF/MEK signaling pathway plays a central role in mediating both proliferation and survival of cancer cells. These proteins are a group of serine/threonine kinases activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface towards both nuclear and cytosolic targets. In combination with several other signaling pathways, they can differentially alter phosphorylation status of the transcription factors. A controlled regulation of these cascades is involved in cell proliferation and differentiation, whereas an unregulated activation of these kinases can result in oncogenesis.

Dysregulation of the RAS/RAF/MEK pathway has been detected in more than 30% of human tumors, however mutations in the MEK1 and MEK2 genes are seldom, so that hyperactivation of MEK1/2 usually results from gain-of-function mutations in RAS and/or B-RAF.

In addition, alteration of the pathways is often associated with drug resistance in the clinic, such as the case of K-RAS mutant expressing tumors.

Since RAS protein is a difficult target, alternative ways altering post-translational modifications using farnesyl transferase inhibitors have been adopted. Drug discovery programs have therefore largely focused on B-RAF and MEK.

In this review we will discuss the most promising strategies developed to target these kinases and the most recent inhibitors facing the preclinical and clinical setting, also considering their structure-activity relationship (SAR).

Keywords: MAPK inhibitors, RAF, MEK, intracellular signalling, kinases, small molecule inhibitors, ATP competitive, ATP non, ATP non competitive, competitive, allosteric inhibitors, mutant B-RAF