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
Current Topics in Medicinal Chemistry
Title: Progress Towards Therapeutic Small Molecule MEK Inhibitors for Use in Cancer Therapy
Volume: 5 Issue: 2
Author(s): Eli M. Wallace, Joseph P. Lyssikatos, Tammie Yeh, James D. Winkler and Kevin Koch
Affiliation:
Keywords: mek inhibitor, erk, arry-142886 (azd 6244), pd 0325901, ci-1040, cancer, map kinase, kinase inhibitor
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.
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Wallace M. Eli, Lyssikatos P. Joseph, Yeh Tammie, Winkler D. James and Koch Kevin, Progress Towards Therapeutic Small Molecule MEK Inhibitors for Use in Cancer Therapy, Current Topics in Medicinal Chemistry 2005; 5 (2) . https://dx.doi.org/10.2174/1568026053507723
DOI https://dx.doi.org/10.2174/1568026053507723 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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