Tyrphostins. 3. Structure-activity relationship studies of .alpha.-substituted benzylidenemalononitrile 5-S-aryltyrphostins

Gazit, Aviv; Osherov, Nir; Posner, Israel; Bar-Sinai, Allan; Gilon, Chaim; Levitzki, Alexander

doi:10.1021/jm00075a010

Cited by 35 publications

(25 citation statements)

References 9 publications

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“…The inhibition of various kinases by PP1 and PP2 is described. The assays were conducted as described in Section 2 and as described in [31] (for EGFR), [28] (for PDGFR), and [32] (for PKA and PKB).…”

Section: Resultsmentioning

confidence: 99%

The pp60^c‐Src inhibitor PP1 is non‐competitive against ATP

et al. 2003

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Glutathione-S-transferase (GST)-pp60 cÀSrc (GSTSrc) expressed in Escherichia coli is as catalytically active as puri¢ed, activated pp60 cÀSrc protein derived from human platelets. We utilized the bacterially expressed enzyme, together with information about the structures of Src family kinases in complex with their inhibitors PP1 and PP2, to modify PP1 in a quest for improved inhibitors. Despite the detailed structural information on Hck-PP1 and Lck-PP2 complexes, which shows that PP1 and PP2 bind to the adenosine triphosphate (ATP) pocket, we were unable to improve the a⁄nity between modi¢ed PP1 and Src. Puzzled, we examined in detail the mechanism by which PP1 inhibits the kinase activity of Src. Here we report that PP1 is non-competitive with ATP for the inhibition of Src, at variance with what is currently accepted, and is a 'mixed competitive inhibitor' vis-a '-vis the substrate. These ¢ndings shed new light on the mechanism whereby PP1-like molecules inhibit Src. Examination of the homology between the kinase domain of Src and those of Hck and Lck reveals signi¢cant di¡erences outside the ATP binding pocket, whereas they are identical within the ATP binding domain. These results suggest that PP1 may be a leading compound for ATP non-competitive inhibitors of Src family kinases. Since Src in its active form is the hallmark of numerous cancers, understanding how PP1 inhibits activated Src will aid in the discovery of potent and selective Src kinase inhibitors. ß

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Section: Resultsmentioning

confidence: 99%

The pp60^c‐Src inhibitor PP1 is non‐competitive against ATP

et al. 2003

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“…In these experiments, cells were exposed to EGF or HRG and then subjected to lysis and immunoprecipitation by anti-EGFR or anti-Neu antibodies. The tyrosine kinase activity in the immunoprecipitates was inhibited by the tyrphostin AG556, a specific inhibitor of EGFR, and by AG879, which specifically inhibits Neu in various cells (27,(31)(32)(33), including PC12 cells (34).…”

Section: Resultsmentioning

confidence: 99%

Secondary Dimerization between Members of the Epidermal Growth Factor Receptor Family

Gamett¹,

Pearson

Cerione

et al. 1997

Journal of Biological Chemistry

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Growth factor receptors of the epidermal growth factor (EGF) receptor family play pivotal roles in the regulation of cell proliferation and differentiation and are involved in the development of human cancers. It has been well documented that these receptors undergo growth factor-stimulated homo-and heterodimerization as a first step in the initiation of signaling cascades. Here we provide evidence for a new mechanism for growth factor-stimulated receptor dimer formation, designated secondary dimerization. The growth factor-induced dimerization and ensuing receptor trans-autophosphorylation results in the dissociation of the original (primary) receptor dimer. Each phosphorylated receptor monomer then interacts with a new (nonphosphorylated) receptor to form a secondary dimer. Treatment of cells with EGF yields Neu-ErbB3 secondary dimers, and heregulin treatment induces the formation of Neu-EGF receptor (secondary) dimers. The ability of EGF and heregulin to stimulate a cascade of dimerization events points to a novel mechanism by which multiple signaling activities and diverse biological responses are initiated by members of the EGF receptor family.

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“…6), a Janus kinase (JAK) inhibitor did not alter CML cell proliferation [98]. The JAK/signal transducer and activator of transcription (STAT) pathway has been implicated in EGF receptor autophosphorylation [99] and cyclin (i.e. cdk2) activation [100].…”

Section: Arctigenin -[(3r 4r)-4-[3 4-dimethoxyphenyl) Methyl] Dihydmentioning

confidence: 99%

Small Molecular Weight Inhibitors of Stress-Activated and Mitogen- Activated Protein Kinases

Malemud

2006

MRMC

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The stress-activated protein kinase (SAPK) and mitogen-activated protein kinase (MAPK) sub-families are crucial to environmental stress responses and responses to growth factors that cause transcriptional activation of genes required for cell proliferation, differentiation and programmed cell death. Small molecular compounds with specific structure/activity characteristics have been developed that competitively block SAPK/MAPK binding to ATP. Chemically modified compounds based on ATP binding pocket characteristics have improved selectivity and specificity for SAPK/MAPK isoforms. In addition, site-specific mutagenesis of MAPKs has helped identify the MAPK structures required for binding recognition and selectivity of these inhibitors. A group of extracellular-signal regulated protein kinase (ERK) inhibitors has been constructed based almost exclusively on their ability to inhibit the ERK activation cascade. Inhibitors have been employed in vitro to identify protein targets and mechanism of action of SAPKs/MAPKs. The efficacy of SAPK/MAPK inhibitors in animal models of inflammation, arthritis, heart failure, cancer and neurological degeneration has provided the impetus for using them in human studies of inflammation and in clinical trials.

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Tyrphostins. 3. Structure-activity relationship studies of .alpha.-substituted benzylidenemalononitrile 5-S-aryltyrphostins

Cited by 35 publications

References 9 publications

The pp60^c‐Src inhibitor PP1 is non‐competitive against ATP

The pp60^c‐Src inhibitor PP1 is non‐competitive against ATP

Secondary Dimerization between Members of the Epidermal Growth Factor Receptor Family

Small Molecular Weight Inhibitors of Stress-Activated and Mitogen- Activated Protein Kinases

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Tyrphostins. 3. Structure-activity relationship studies of .alpha.-substituted benzylidenemalononitrile 5-S-aryltyrphostins

Cited by 35 publications

References 9 publications

The pp60c‐Src inhibitor PP1 is non‐competitive against ATP

The pp60c‐Src inhibitor PP1 is non‐competitive against ATP

Secondary Dimerization between Members of the Epidermal Growth Factor Receptor Family

Small Molecular Weight Inhibitors of Stress-Activated and Mitogen- Activated Protein Kinases

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Product

Resources

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The pp60^c‐Src inhibitor PP1 is non‐competitive against ATP

The pp60^c‐Src inhibitor PP1 is non‐competitive against ATP