Progress Towards Therapeutic Small Molecule MEK Inhibitors for Use in Cancer Therapy

Abstract

This paper reviews recent progress in the design and evaluation of MEK inhibitors as cancer therapeutics. Activation of the Ras / Raf / MEK / MAP kinase pathway has been implicated in uncontrolled cell proliferation and tumor growth. Mutated, oncogenic forms of Ras are found in 50% of colon, 90% of pancreatic and 30% of lung cancers. Recently, B-Raf mutations have been identified in more than 60% of malignant melanomas and from 40-70% of papillary thyroid cancers. MEK, a dual specificity kinase, is a key player in this pathway; it is downstream of both Ras and Raf and activates ERK1/2 through phosphorylation of key tyrosine and threonine residues. Representative examples of both ATP competitive and non-competitive inhibitors as well as natural product based inhibitors will be discussed.

Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: Potential proinflammatory mechanisms

“…Array BioPharma (Boulder, CO) is also developing potent and selective MEK inhibitors (16) and has reported significant efficacy data in animal models of inflammation and arthritis (51), further supporting the pivotal role of this kinase in inflammatory diseases.…”

“…Although it is known to be activated by a wide variety of stimuli, the ERK pathway is frequently characterized as being important primarily in mitogenand growth factor-induced effects on the cell cycle (8). The role of MEK in cellular proliferation and apoptosis is indeed well validated, and this knowledge led to the initial investigations into the use of MEK (or upstream Raf) inhibitors for treating cancers (15,16). A common generalization, however, is that JNK and p38 are the main drivers behind the pathophysiology of inflammation-mediated diseases, while proliferative, neoplastic responses are the domain of the MEK/ERK pathway (8,9).…”

Diet, Autophagy, and Cancer: A Review

“…This action of the triterpenoid soyasaponins was accompanied by inactivation of Akt kinase and was dependent on the activation of the MEK/ERK1/2 pathway (183). This requirement for ERK1/2 activation in the induction of autophagic cell death by curcumin and soyasaponin triterpenoids seems to be paradoxical because this mitogen-activated protein kinase has frequently been depicted as a stimulator of cell proliferation and tumorigenesis (184). Yet, a similar requirement for Raf-1/MEK/ERK1/2 activity in the drug-and starvation-dependent induction of autophagy has been observed in human colon cancer cells.…”

Selective inhibition of MEK1/2 reveals a differential requirement for ERK1/2 signalling in the regulation of HIF-1 in response to hypoxia and IGF-1

“…Constitutive activation of the Ras/Raf/ERK1/2 pathway leads to the transformation of mammalian cells, and enhanced activity of this pathway occurs in many human cancers (Garnett and Marais, 2004;Wallace et al, 2005). Activation of the Ras/Raf/ERK1/2 pathway may also control tumour growth by regulating HIF-1-mediated angiogenesis and glucose metabolism.…”