The Role of 4-phosphonodifluoromethyl- and 4-phosphono-phenylalanine in the selectivity and cellular uptake of SH2 domain ligands

Stankovic, Charles J.; Surendran, Narayanan; Lunney, Elizabeth A.; Plummer, Mark S.; Para, Kimberly S.; Shahripour, Aurash; Fergus, James H.; Marks, James S.; Herrera, Román; Hubbell, Susan; Humblet, Christine; Saltiel, Alan R.; Stewart, Barbra H.; Sawyer, Tomi K.

doi:10.1016/s0960-894x(97)00334-x

Cited by 47 publications

(40 citation statements)

References 30 publications

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“…The phosphotyrosine residue itself can be replaced by mimics containing phosphonates, phosphinates or one or more carboxylates that are insensitive to phosphotyrosine phosphatase activity (Burke and Lee, 2003;Sundaramoorthi et al, 2003). Furthermore, the anionic nature of the phosphate or phosphonate can be masked through the formation of esters that allow penetration of the compound through biological membranes (Stankovic et al, 1997;Rickles et al, 1998). These advances should allow, in the near future, ready access to stable inhibitors designed to penetrate cells and target the SH2 domains of hematopoietic cell kinases that will be as useful to investigators as inhibitors targeted to the catalytic domains.…”

Section: Inhibitors Directed Against the Sh2 Domainmentioning

confidence: 99%

Molecular interdiction of Src-family kinase signaling in hematopoietic cells

2004

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Section: Inhibitors Directed Against the Sh2 Domainmentioning

confidence: 99%

Molecular interdiction of Src-family kinase signaling in hematopoietic cells

2004

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“…This observation allowed researchers to consider replacement of the D-Hcy-NH 2 fragment with peptidomimetics [189,193,198]. This proved to be a successful strategy, in particular the Interestingly, enhanced affinity could be obtained by modifying the amino terminus, in particular the para-nitro phenyl group (IC 50 = 3.8 µM) led to enhanced binding affinity (compare compounds 26 and 28) [198].…”

Section: Design Of Inhibitors For the Src Sh2 Domainmentioning

confidence: 99%

“…The crystral structure of a non-peptide "de novo" inhibitor bound to the Src SH2 domian. or stability to intracellular phosphatases [182,[189][190][191][195][196].…”

Section: Design Of Inhibitors For the Src Sh2 Domainmentioning

confidence: 99%

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Progress in the Development of Inhibitors of SH2 Domains

Cody¹,

Lin²,

Panek³

et al. 2000

CPD

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SH2 domains are discrete structural motifs common to a variety of critical intracellular signaling proteins. Inhibitors of specific SH2 domains have become important therapeutic targets in the treatment and/or prevention of restenosis, cancers (including small cell lung), cardiovascular disease, osteoporosis, apoptosis among others. Considering the social and economic impact of these diseases significant attention has been focused on the development of potent and selective inhibitors of specific SH2 domains. In particular, considerable research has been performed on Src, PI 3-kinase, Grb2 and more recently, Lck. In this review, we will focus on progress in the development of inhibitors for these specific SH2 domains and evaluate potential future targets.

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“…Furthermore, the delivery techniques mentioned are not applicable for in vivo studies. Since masking the negative charges by a prodrug approach was of limited success [61], various efforts have been undertaken towards nonphosphorous containing pTyr mimetics. Based on the pionieering work of Sikorski et al [62], who demonstrated the utility of the malonate moiety as a phosphate replacement in 4,5-dideoxyshikimate-3-phosphate, O-malonyl-L-tyrosine (OMT, 25) [58] and its 2-fluoromalonyl variant 26 (FOMT) [63] were introduced as non phosphorous containing pTyr mimetics.…”

Section: Grb2-sh2 Binding Peptides Containing Phosphotyrosine Mimeticsmentioning

confidence: 99%

Structure-based Design of Compounds Inhibiting Grb2-SH2 Mediated Protein-protein Interactions in Signal Transduction Pathways

Fretz

Furet

García‐Echeverría

et al. 2000

CPD

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Receptor protein tyrosine kinases are usually activated upon binding their growth factors, or other suitable ligands, to their extracellular domains. These activated receptors initiate cytoplasmic signalling cascades which, when aberrant, can result in different disease states, such as oncogenic transformation. Many receptor protein tyrosine kinases use Src homology 2 domains (SH2) to couple growth factor activation with intracellular signalling pathways to mediate cell control and other biological events. The characterization of the components involved in these signal transduction pathways has resulted in the identification of new attractive targets for therapeutic intervention. Such is the case for the protein-protein interactions involving the SH2 domain of growth factor receptor bound protein 2 (Grb2). Agents that specifically disrupt Grb2-SH2 binding interactions involved in aberrant signalling could potentially shut down these oncogenic pathways and thus block human malignancies. This paper reviews the structural characteristics of the Grb2-SH2 domain and the approaches which have been used to identify antagonists of the Grb2-SH2 domain. Examples have been selected from our own research to illustrate how the unique structural features of the ligand-bound Grb2-SH2 have been exploited to design potent and selective Grb2-SH2 antagonists.

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The Role of 4-phosphonodifluoromethyl- and 4-phosphono-phenylalanine in the selectivity and cellular uptake of SH2 domain ligands

Cited by 47 publications

References 30 publications

Molecular interdiction of Src-family kinase signaling in hematopoietic cells

Molecular interdiction of Src-family kinase signaling in hematopoietic cells

Progress in the Development of Inhibitors of SH2 Domains

Structure-based Design of Compounds Inhibiting Grb2-SH2 Mediated Protein-protein Interactions in Signal Transduction Pathways

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