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

Authors: Wallace, Eli M.¹; Lyssikatos, Joseph P.¹; Yeh, Tammie¹; Winkler, James D.¹; Koch, Kevin¹

Source: Current Topics in Medicinal Chemistry, Volume 5, Number 2, April 2005 , pp. 215-229(15)

Publisher: Bentham Science Publishers

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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.

Keywords: mek inhibitor; erk; arry-142886 (azd 6244); pd 0325901; ci-1040; cancer; map kinase; kinase inhibitor

Document Type: Review article

DOI: 10.2174/1568026053507723

Affiliations: 1: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA.

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