Design and synthesis of novel photoaffinity reagents for labeling VEGF receptor tyrosine kinases

Han, Sun‐Young; Choi, Seo Hyun; Kim, Myung Hee; Lee, Woo Ghil; Kim, Seong Hwan; Min, Yong Ki; Kim, Bum Tae

doi:10.1016/j.tetlet.2006.02.119

Cited by 13 publications

(6 citation statements)

References 26 publications

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“…The identification tag can be a fluorescent dye, a radioisotope or a partner for a specific binding event (e.g., biotin–avidin). The length of the linker/spacer groups between functionalities is a key component in photoaffinity probes [7]. Too short a linker may lead to the probe cross-linking with itself while too long a linker may place the photoreactive group at too great a distance to capture the target protein efficiently.…”

Section: Photoaffinity Probe Designmentioning

confidence: 99%

Photoaffinity Labeling in Target- and Binding-Site Identification

2015

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Photoaffinity labeling (PAL) using a chemical probe to covalently bind its target in response to activation by light has become a frequently used tool in drug discovery for identifying new drug targets and molecular interactions, and for probing the location and structure of binding sites. Methods to identify the specific target proteins of hit molecules from phenotypic screens are highly valuable in early drug discovery. In this review, we summarize the principles of PAL including probe design and experimental techniques for in vitro and live cell investigations. We emphasize the need to optimize and validate probes and highlight examples of the successful application of PAL across multiple disease areas.The use of photoaffinity labeling (PAL) in medicinal chemistry and drug discovery has recently come to fruition [1]. PAL is a powerful technique used for the study of proteinligand interactions, where it can identify unknown targets of ligands, assist in the elucidation of protein structures, functions and conformational changes as well as identify novel or alternative binding sites in proteins [2]. In the current review, we will discuss the general principles of photoaffinity labeling concerning photoaffinity probe design and experimental strategies and the performance of the different photoaffinity groups available. We then focus on examples of the successful application of PAL in relation to the identification of molecular targets of small molecules, discovery of off-target interactions and the classification and structural elucidation of binding sites. The majority of examples presented here were published within the past 15 years, and greater emphasis has been given to recent examples illustrative of the general approaches. Photoaffinity probe designPAL is the use of a chemical probe that can covalently bind to its target in response to activation by light [3]. This is made possible by the incorporation of a photoreactive group within an otherwise reversibly binding probe compound. On irradiation with a specific wavelength of light, the photogroup forms a reactive intermediate that rapidly reacts with and binds to the nearest molecule, which ideally will be the target protein. Frank

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Section: Photoaffinity Probe Designmentioning

confidence: 99%

Photoaffinity Labeling in Target- and Binding-Site Identification

2015

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“…Biotin-tagged photoaffinity probes can be useful not only for the separation of the probe-target protein / peptide complex in mixture (Fig. 3), but also for the indirect visualization of this complex by using the chemiluminescent reaction of horse-radish peroxidase conjugated avidin [22,23].…”

Section: Photoaffinity Probementioning

confidence: 99%

“…To verify the specificity of the observed target proteins, simple experiments such as western blot analysis and competition binding assay were traditionally used [12,23,40]. However, these technologies do not provide quantitative results of the relative sensitivities for the bioactive small molecule to the target protein and these are not enough to turn out the initially identified proteins (or candidates for target proteins) to be a valid target.…”

Section: Target Validation By Surface Plasmon Resonance (Spr) Technologymentioning

confidence: 99%

Introduction to Chemical Proteomics for Drug Discovery and Development

Han

Kim²

2007

Archiv der Pharmazie

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A fundamental goal of chemical proteomics is to identify target proteins for bioactive small molecules and then apply them to drug discovery and development as valid and drugable targets. Here, we introduce integrated technologies for the rapid identification of target proteins, methodologies for validating them as drugable targets, and applications of chemical proteomics in drug discovery and development.

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“…ABPP can be classified as activity-based probes (ABPs) and affinity-based probes (AfBPs) 14 . photoaffinity labelling, as one technique of affinity-based probes, has been used to study various enzyme classes, such as kinases 15 , histone deactylases (HDACs) 16 , phosphodiesterases (PDEs) 17 , and so on ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of a novel photoaffinity probe for labelling EGF receptor tyrosine kinases

Zheng

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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The epidermal growth factor receptor (EGFR) and HER2 are two important tyrosine kinases that play crucial roles in signal transduction pathways that regulate numerous cellular functions including proliferation, differentiation, migration, and angiogenesis. In the past 20 years, many proteomic methods have emerged as powerful methods to evaluate proteins in biological processes and human disease states. Among them, activity-based protein profiling (ABPP) is one useful approach for the functional analysis of proteins. In this study, a novel photoaffinity probe 11 was designed and synthesised to assess the target profiling of the reactive group in the photoaffinity probe 11. Biological evaluation was performed, and the results showed that the novel photoaffinity probe binds to EGFR and HER2 proteins and it hits targets by the reactive group.

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Design and synthesis of novel photoaffinity reagents for labeling VEGF receptor tyrosine kinases

Cited by 13 publications

References 26 publications

Photoaffinity Labeling in Target- and Binding-Site Identification

Photoaffinity Labeling in Target- and Binding-Site Identification

Introduction to Chemical Proteomics for Drug Discovery and Development

Design and synthesis of a novel photoaffinity probe for labelling EGF receptor tyrosine kinases

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