Emerging MEK inhibitors

McCubrey, James A.; Steelman, Linda S.; Abrams, Steven L.; Chappell, William H.; Russo, Suzanne; Ove, Roger; Milella, Michèle; Tafuri, Agostino; Lunghi, Paolo; Bonati, Antonio; Stivala, Franca; Nicoletti, Ferdinando; Libra, Massimo; Martelli, Alberto M.; Montalto, Giuseppe; Cervello, Melchiorre

doi:10.1517/14728210903282760

Cited by 59 publications

(49 citation statements)

References 99 publications

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“…5,6,14 Due to overexpression or mutations of RTKs and mutations in Ras and B-Raf in many human cancers, the pathway has become a major target for cancer drug development. 15,16 Although the amplifier function of the pathway has been suspected, only quantitative experimentation could confirm it. On average, a cell possesses approximately 20,000 Ras molecules, but only 0.3-5% become activated in response to 10% foetal calf serum, and only 30-50% in response to large mitogen doses.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Biology using engineering tools

Birtwistle

Kölch

2011

Cell Cycle

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Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Biology using engineering tools

Birtwistle

Kölch

2011

Cell Cycle

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“…[1][2][3][4][5][6][7][8][9][10][11][12] Mutations can occur in the genes encoding pathway constituents (for example, Ras and Raf), upstream receptors (for example, Kit, Fms and Fms-like tyrosine kinase (Flt)-3) or chromosomal translocations (for example, BCR-ABL and TEL-platelet-derived growth factor receptor (PDGFR)), which activate this pathway. Chemotherapeutic drugs frequently used in leukemia therapy often activate this pathway.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 This pathway relays this information through interactions with various other proteins to the nucleus to control gene expression. [1][2][3][4][5][6][7][8][9][10][11][12] This review will discuss how these pathways may be aberrantly regulated in leukemia and contribute to therapeutic sensitivity/resistance and in some cases poor prognosis. [4][5]13 Inhibition of Ras (or Ras-related molecules), Raf, MEK and ERK may prove useful in leukemia treatment.…”

Section: Introductionmentioning

confidence: 99%

Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy

et al. 2011

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“…Therefore, stringent control over ERK interactions with substrate proteins and efficient phosphate transfer are essential for maintaining normal cell physiology. However, unregulated activation of the ERK1/2 pathway is often observed in a variety of cancers, which contributes to the uncontrolled cell proliferation, survival, and resistance to anticancer drugs (7)(8)(9)(10). Thus, a better understanding of the mechanisms regulating ERK interactions with substrates may aide in the discovery of ERK-targeted chemotherapeutics that selectively regulate substrates involved in proliferation while preserving other ERK functions in normal cells.…”

mentioning

confidence: 99%

Quantitative Analysis of ERK2 Interactions with Substrate Proteins

Burkhard

Chen

Shapiro

2011

Journal of Biological Chemistry

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Extracellular signal-regulated kinase-1 and -2 (ERK1/2) proteins regulate a variety of cellular functions, including cell proliferation and differentiation, by interacting with and phosphorylating substrate proteins. Two docking sites, common docking (CD/ED) domain and F-site recruitment site (FRS), on ERK proteins have been identified. Specific interactions with the CD/ED domain and the FRS occur with substrates containing a docking site for ERK and JNK, LXL (DEJL) motif (D-domain) and a docking site for ERK, FXF (DEF) motif (F-site), respectively. However, the relative contributions of the ERK docking sites in mediating substrate interactions that allow efficient phosphate transfer are largely unknown. In these studies, we provide a quantitative analysis of ERK2 interactions with substrates using surface plasmon resonance to measure real time protein-protein interactions. ERK2 interacted with ELK-1 (DEF and DEJL motifs), RSK-1 (DEJL motif), and c-Fos (DEF motif) with K D values of 0.25, 0.15, and 0.97 M, respectively. CD/ED domain mutations inhibited interactions with ELK-1 and RSK-1 by 6-fold but had no effect on interactions with c-Fos. Select mutations in FRS residues differentially inhibited ELK-1 or c-Fos interactions with ERK2 but had little effect on RSK-1 interactions. Mutations in both the ED and FRS docking sites completely inhibited ELK-1 interactions but had no effect on interactions with stathmin, an ERK substrate whose docking site is unknown. The phosphorylation status of ERK2 did not affect interactions with RSK-1 or c-Fos but did inhibit interactions with ELK-1 and stathmin. These studies provide a quantitative evaluation of specific docking domains involved in mediating interactions between ERK2 and protein substrates and define the contributions of these interactions to phosphate transfer.The major members of the mitogen-activated protein kinase (MAPK) family consist of the extracellular signal-regulated kinases-1 and -2 (ERK1/2), c-Jun N-terminal kinases (JNKs), p38 mitogen-activated protein kinases, and ERK5 (1). ERK1/2 proteins are serine/threonine kinases involved in signal transduction pathways that mediate cellular proliferation and differentiation in response to growth factors and hormones (2). In vitro studies suggest that ERK1/2 can interact with and phosphorylate over 160 substrates, implicating their involvement in a diverse number of cellular functions (3-6). Therefore, stringent control over ERK interactions with substrate proteins and efficient phosphate transfer are essential for maintaining normal cell physiology. However, unregulated activation of the ERK1/2 pathway is often observed in a variety of cancers, which contributes to the uncontrolled cell proliferation, survival, and resistance to anticancer drugs (7-10). Thus, a better understanding of the mechanisms regulating ERK interactions with substrates may aide in the discovery of ERK-targeted chemotherapeutics that selectively regulate substrates involved in proliferation while preserving other ERK functions in normal c...

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Emerging MEK inhibitors

Abstract: Targeting MEK has been shown to be effective in suppressing many important pathways involved in cell growth and the prevention of apoptosis. MEK inhibitors have many potential therapeutic uses in the suppression of cancer, proliferative diseases and aging.

Cited by 59 publications

References 99 publications

Biology using engineering tools

Biology using engineering tools

Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy

Quantitative Analysis of ERK2 Interactions with Substrate Proteins

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