title: 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.
authors.affiliation: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. Eli.Wallace@arraybiopharma.com
authors.forename: Eli M
authors.initials: EM
authors.lastname: Wallace
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
authors.forename: Tammie
authors.initials: T
authors.lastname: Yeh
authors.forename: James D
authors.initials: JD
authors.lastname: Winkler
authors.forename: Kevin
authors.initials: K
authors.lastname: Koch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001685:Biological Factors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001685:Biological Factors; D004791:Enzyme Inhibitors; D020930:MAP Kinase Kinase Kinases