Beyond the MEK-pocket: Can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK?

Tecle, Haile; Shao, Jianxing; Li, Yanhong; Kothe, Michael; Kazmirski, Steven L.; Penzotti, Julie E.; Ding, Yuanhua; Ohren, Jeffrey F.; Moshinsky, Deb; Coli, Rocco; Jhawar, Nidhi; Bora, Emilia; Jacques-O’Hagan, Suzanne; Wu, Joe C.

doi:10.1016/j.bmcl.2008.10.108

Cited by 35 publications

(25 citation statements)

References 11 publications

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“…The C-ring of the coumarin core extends out towards solvent and interacts with ARG234 and ARG227 on the solvent accessible surface of MEK1. The terminal nitrogen of the sulphonyl-urea provides an optimal vector for attaching a covalent linker as it extends into a previously reported solvent accessible surface on MEK [40]. Accordingly, in these initial studies we designed structurally modified analogs of MEK and PI3K inhibitors based on these core structures ( Figure 3 ) for subsequent covalent linking to produce a dual MEK/PI3K inhibitor as a single chemical entity.…”

Section: Resultsmentioning

confidence: 99%

Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor

Dort

Galbán

Wang

et al. 2015

Bioorganic & Medicinal Chemistry

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The MAP kinase (Ras/MEK/ERK) and PI3K/Akt/mTOR oncogenic signaling pathways are central regulators of KRAS-mediated transformation. Molecular reciprocity between the Ras/MEK/ERK and PI3K/Akt/mTOR pathways provides cancer cells with the ability to evade treatment when targeting only one pathway with monotherapy. Multi-kinase targeting was explored through the development of a single bivalent chemical entity by covalent linking of high-affinity MEK and PI3K inhibitors. A prototype dual-acting agent (compound 8) designed using the PI3K inhibitor ZSTK474 and the Raf/MEK inhibitor RO5126766 as scaffolds displayed high in vitro inhibition of both PI3K (IC50 = 172 nM) and MEK1 (IC50 = 473 nM). Additionally, compound 8 demonstrated significant modulation of MEK and PI3K signaling pathway activity in human A549 human lung adenocarcinoma cells and pancreatic cancer cells (PANC-1) and also decreased cellular viability in these two cell lines.

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Section: Resultsmentioning

confidence: 99%

Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor

Dort

Galbán

Wang

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Two considerations may account for this discrepancy. First, the published crystal structures of recombinant Mek1 were solved from proteins with amino-terminal truncations (16,24,48,59). The extents of these truncations varied, but all removed the Erk-binding/docking domain of Mek1.…”

Section: Discussionmentioning

confidence: 99%

A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

Turski

Brady

Kim

et al. 2012

Molecular and Cellular Biology

251

218

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c Copper (Cu) is essential for development and proliferation, yet the cellular requirements for Cu in these processes are not well defined. We report that Cu plays an unanticipated role in the mitogen-activated protein (MAP) kinase pathway. Ablation of the Ctr1 high-affinity Cu transporter in flies and mouse cells, mutation of Ctr1, and Cu chelators all reduce the ability of the MAP kinase kinase Mek1 to phosphorylate the MAP kinase Erk. Moreover, mice bearing a cardiac-tissue-specific knockout of Ctr1 are deficient in Erk phosphorylation in cardiac tissue. In vitro investigations reveal that recombinant Mek1 binds two Cu atoms with high affinity and that Cu enhances Mek1 phosphorylation of Erk in a dose-dependent fashion. Coimmunoprecipitation experiments suggest that Cu is important for promoting the Mek1-Erk physical interaction that precedes the phosphorylation of Erk by Mek1. These results demonstrate a role for Ctr1 and Cu in activating a pathway well known to play a key role in normal physiology and in cancer. Copper (Cu) is a metal ion that functions as a redox-active cofactor for a broad range of biochemical reactions, including mitochondrial oxidative phosphorylation, protection from reactive oxygen species, connective tissue maturation, iron absorption, neuropeptide biogenesis, and other processes (28, 43). Numerous studies point to the essentiality of Cu for normal growth and development, while aberrant Cu accumulation in tissues, as manifested in Wilson's disease patients, results in significant pathologies (33,35,42,47,60,61). However, the precise roles Cu plays and the mechanistic processes by which Cu drives cellular proliferation and growth are not well understood.The Ras/mitogen-activated protein kinase (MAPK) signaling pathway is an evolutionarily conserved pathway involved in the control of many fundamental biological processes, including cell proliferation, apoptosis, survival, differentiation, motility, and metabolism (26,30). Aberrant Ras/MAPK signaling has significant consequences; loss of function of several components of the Ras/MAPK signaling cascade results in lethality, whereas gain-offunction mutations in many of the Ras/MAPK signaling components underlie cancer (2,12,26,55).Here we identify the Ctr1 high-affinity Cu ϩ transporter, conserved from yeast to humans, as being important for stimulation of the MAPK Erk in response to extracellular growth factor-mediated activation of the Ras signaling pathway. Moreover, genetic, physiological, and biochemical experiments point to a direct role for Cu in the ability of the MAPK kinase Mek1 to phosphorylate Erk in fruit flies, cultured cells, and mice. These studies suggest that the MAPK signaling pathway is a key cellular proliferation pathway that is stimulated by Cu and may be a direct target of potent cancer chemotherapeutics that function via Cu chelation. MATERIALS AND METHODS Drosophila melanogaster stocks and crosses. Phantom Gal4, UAS mCD8::GFP/TM6, Tb flies were from Michael O'Connor, University of Minnesota (44). The UAS-Ctr1ARNA...

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“…Some kinases also contain allosteric sites, pockets remote from the ATP binding site into which inhibitors can bind, altering the overall conformation of the catalytic domain and inhibiting the enzyme (Fig. 6) [41,90,134]. These may be more easily targeted by small molecules than substrate binding sites as they do not involve disrupting protein-protein interactions, but not all kinases have a known suitable allosteric site.…”

Section: Protein Kinase Structure and Selective Inhibitionmentioning

confidence: 99%

Measuring and interpreting the selectivity of protein kinase inhibitors

2009

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Protein kinase inhibitors are a well-established class of clinically useful drugs, particularly for the treatment of cancer. Achieving inhibitor selectivity for particular protein kinases often remains a significant challenge in the development of new small molecules as drugs or as tools for chemical biology research. This review summarises the methodologies available for measuring kinase inhibitor selectivity, both in vitro and in cells. The interpretation of kinase inhibitor selectivity data is discussed, particularly with reference to the structural biology of the protein targets. Measurement and prediction of kinase inhibitor selectivity will be important for the development of new multi-targeted kinase inhibitors.

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Beyond the MEK-pocket: Can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK?

Cited by 35 publications

References 11 publications

Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor

Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor

A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling

Measuring and interpreting the selectivity of protein kinase inhibitors

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