Phosphotyrosyl Mimetics in the Development of Signal Transduction Inhibitors

Burke, Terrence R.; Lee, Kyeong

doi:10.1021/ar020127o

Cited by 125 publications

(71 citation statements)

References 82 publications

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“…The potency of DFMP as a PTP pharmacophore has been extensively analyzed (9,15,29,30). Burke et al (9) and Burke and Lee (29) have shown that the DFMP group contributes to high PTP binding affinity.…”

Section: Tablementioning

confidence: 99%

Section: Tablementioning

confidence: 99%

“…Burke et al (9) and Burke and Lee (29) have shown that the DFMP group contributes to high PTP binding affinity. Its use in the phosphonodifluoromethyl-phenylalanine peptide inhibitors demonstrated that the difluoro group can increase PTP binding by 1000-fold relative to the monofluorinated counterpart (9,29). This is also the case for the non-peptide inhibitors, where the DFMP inhibitors are considerably more potent than their mono-and non-fluorinated counterparts (29).…”

Section: Tablementioning

confidence: 99%

“…Its use in the phosphonodifluoromethyl-phenylalanine peptide inhibitors demonstrated that the difluoro group can increase PTP binding by 1000-fold relative to the monofluorinated counterpart (9,29). This is also the case for the non-peptide inhibitors, where the DFMP inhibitors are considerably more potent than their mono-and non-fluorinated counterparts (29). The fluorines also contribute to inhibitor selectivity whereby the DFMP inhibitors are highly selective for PTP1B and T-cell PTP and lose selectivity with decreased ␣-fluorination (15).…”

Section: Tablementioning

confidence: 99%

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Residues Distant from the Active Site Influence Protein-tyrosine Phosphatase 1B Inhibitor Binding

Montalibet

Skorey²,

McKay

et al. 2006

Journal of Biological Chemistry

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Regions of protein-tyrosine phosphatase (PTP) 1B that are distant from the active site yet affect inhibitor binding were identified by a novel library screen. This screen was based on the observation that expression of v-Src in yeast leads to lethality, which can be rescued by the coexpression of PTP1B. However, this rescue is lost when yeast are grown in the presence of PTP1B inhibitors. To identify regions of PTP1B (amino acids 1-400, catalytic domain plus 80-amino acid C-terminal tail) that can affect the binding of the difluoromethyl phosphonate (DFMP) inhibitor 7-bromo-6-difluoromethylphosphonate 3-naphthalenenitrile, a library coexpressing PTP1B mutants and v-Src was generated, and the ability of yeast to grow in the presence of the inhibitor was evaluated. PTP1B inhibitor-resistant mutations were found to concentrate on helix ␣7 and its surrounding region, but not in the active site. No resistant amino acid substitutions were found to occur in the C-terminal tail, suggesting that this region has little effect on active-site inhibitor binding. An in-depth characterization of a resistant substitution localizing to region ␣7 (S295F) revealed that this change minimally affected enzyme catalytic activity, but significantly reduced the potency of a panel of structurally diverse DFMP PTP1B inhibitors. This loss of inhibitor potency was found to be due to the difluoro moiety of these inhibitors because only the difluoro inhibitors were shifted. For example, the inhibitor potency of a monofluorinated or non-fluorinated analog of one of these DFMP inhibitors was only minimally affected. Using this type of library screen, which can scan the nearly full-length PTP1B sequence (catalytic domain and C-terminal tail) for effects on inhibitor binding, we have been able to identify novel regions of PTP1B that specifically affect the binding of DFMP inhibitors.A traditional approach to understanding the structural interactions between an inhibitor and enzyme is through crystallographic studies of the inhibitor-enzyme complex. Solving the three-dimensional structure of such complexes can identify the key residues that interact with the inhibitor, providing an understanding of the mechanism of inhibition. This is normally accompanied by site-directed mutagenesis of the interacting residues to validate their role in inhibitor binding and to determine the degree to which this interaction contributes to inhibitor potency. Such structures are also important in drug design, as they allow the identification of potential interactions that could improve inhibitor potency using further chemical modifications.Protein-tyrosine phosphatase (PTP) 3 1B (EC 3.1.3.48), a potential drug target for the treatment of diabetes and obesity (1, 2), has had a number of published inhibitor-enzyme complexes, and the determinants required for the binding of various inhibitors have been identified. Because these inhibitors all target the active site, the determinants identified are located in the active-site region. Fig. 4).Because of the static nature...

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Section: Tablementioning

confidence: 99%

Section: Tablementioning

confidence: 99%

Section: Tablementioning

confidence: 99%

Section: Tablementioning

confidence: 99%

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Residues Distant from the Active Site Influence Protein-tyrosine Phosphatase 1B Inhibitor Binding

Montalibet

Skorey²,

McKay

et al. 2006

Journal of Biological Chemistry

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“…In the previous studies, one of the directions in designing the inhibitors has focused on the synthesis of enzymatically stable phosphotyrosine mimics (pTyr) which contain the fragments of (phosphonomethyl)phenylalanine (Pmp) 1a and its fluoro-substituted analogues 1b, c [3][4][5][6]. However, there is a limitation in the development of the low molecular PTP inhibitors due to several problems including the selectivity and cell permeability.…”

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confidence: 99%

α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases

Khavrienko¹,

Kobzar²,

Shevchuk³

et al. 2014

Dopov. Nac. akad. nauk Ukr.

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of the RAS I. P. Beletskaya, Corresponding Member of the NAS of Ukraine A. I. Vovk, Academician of the NAS of Ukraine V. P. Kukhar α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatasesThe present study offers a new approach for designing inhibitors of protein tyrosine phosphatases. We have synthesized the cyclam derivatives with α,α-difluoro-β-ketophosphonate fragments covalently attached to tetraazamacrocyclic scaffold, which is known to be of medical interest. The obtained functionalized macrocycles were evaluated as inhibitors of PTP1B, TC-PTP, CD45, and other protein tyrosine phosphatases.

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Combinatorial Libraries: Applications in Chemical Biology

Nestler¹

2008

Wiley Encyclopedia of Chemical Biology

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The sequencing of genomes gave access to the complete set of building blocks for organisms of various species. A plethora of “‐omics” technologies has been developed to investigate the dynamic interactions of the building blocks to understand the functioning of living organisms. Synthetic molecules have proven to be powerful tools to modulate that states of biological systems, but the challenges to find suitable probes are tremendous. Combinatorial libraries allow preparing and testing diverse sets of molecules with high efficiency. In this article, we will discuss how combinatorial chemistry enables to investigate and modulate biochemical function in the quest to chart chemical and biological spaces.

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Phosphotyrosyl Mimetics in the Development of Signal Transduction Inhibitors

Cited by 125 publications

References 82 publications

Residues Distant from the Active Site Influence Protein-tyrosine Phosphatase 1B Inhibitor Binding

Residues Distant from the Active Site Influence Protein-tyrosine Phosphatase 1B Inhibitor Binding

α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases

Combinatorial Libraries: Applications in Chemical Biology

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