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A new affinity probe targeting VEGF receptors for kinase inhibitor selectivity profiling by chemical proteomics.
MedLine Citation:
PMID:  24712744     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Solid tumors are dependent for growth on nutrients and the supply of oxygen, which they often acquire via neoangiogenesis. Vascular Endothelial Growth Factors and the corresponding receptors (VEGFRs) play central roles in this process and consequently, the blockade of this pathway is one therapeutic strategy for cancer treatment. A number of small molecules inhibiting VEGFR inhibitors have been developed for clinical use and a comprehensive view of target selectivity is important to assess the therapeutic as well as risk potential of a drug molecule. Recent advances in mass spectrometry-based chemical proteomics allow analyses of drug-target interactions under close-to-physiological conditions and in this study, we report on the design, synthesis and application of a small molecule affinity probe as a tool for the selectivity profiling of VEGFR and other kinase inhibitors. The probe is capable of binding >132 protein kinases, including angiokinases such as VEGFRs, PDGFRs and c-KIT from lysates of cancer cell lines or human placenta tissue. Combining the new probe with Kinobeads in competitive binding assays, we were able to identify nanomolar off-targets of the VEGFR/PDGFR inhibitors Pazopanib and Axitinib. Because of its broad binding spectrum, the developed chemical tool can be generically used for the discovery of kinase inhibitor targets which may contribute to a more comprehensive understanding of the mechanisms of action of such drugs.
Authors:
Xin Ku; Stephanie Heinzlmeir; Dominic Helm; Guillaume Médard; Bernhard Kuster
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-4-9
Journal Detail:
Title:  Journal of proteome research     Volume:  -     ISSN:  1535-3907     ISO Abbreviation:  J. Proteome Res.     Publication Date:  2014 Apr 
Date Detail:
Created Date:  2014-4-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101128775     Medline TA:  J Proteome Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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