Abstract
Mass spectrometry-based technologies are increasingly utilized in drug discovery. Phosphoproteomics in particular has allowed for the efficient surveying of phosphotyrosine signaling pathways involved in various diseases states, most prominently in cancer. We describe a phosphotyrosine-based proteomics screening approach to identify signaling pathways and tyrosine kinase inhibitor targets in highly tumorigenic human lymphoma-like primary cells. We identified several receptor tyrosine kinase pathways and validated SRC family kinases (SFKs) as potential drug targets for targeted selection of small molecule inhibitors. BMS-354825 (dasatinib) and SKI-606 (bosutinib), second and third generation clinical SFK/ABL inhibitors, were found to be potent cytotoxic agents against tumorigenic cells with low toxicity to normal pediatric stem cells. Both SFK inhibitors reduced ERK1/2 and AKT phosphorylation and induced apoptosis. This study supports the adaptation of high-end mass spectrometry techniques for the efficient identification of candidate tyrosine kinases as novel therapeutic targets in primary cancer cell lines.
Keywords: Bosutinib, BMS-354825, dasatinib, kinase inhibitors, phosphoproteomics, SKI-606, Src family kinases.
Current Drug Discovery Technologies
Title:A Phosphoproteomics Approach to Identify Candidate Kinase Inhibitor Pathway Targets in Lymphoma-Like Primary Cell Lines
Volume: 10 Issue: 4
Author(s): Miliana Vojvodic, Loen M. Hansford, Olena Morozova, Kim M. Blakely, Paul Taylor, Kelly E. Fathers, Jason Moffat, Marco Marra, Kristen M. Smith, Michael F. Moran and David R. Kaplan
Affiliation:
Keywords: Bosutinib, BMS-354825, dasatinib, kinase inhibitors, phosphoproteomics, SKI-606, Src family kinases.
Abstract: Mass spectrometry-based technologies are increasingly utilized in drug discovery. Phosphoproteomics in particular has allowed for the efficient surveying of phosphotyrosine signaling pathways involved in various diseases states, most prominently in cancer. We describe a phosphotyrosine-based proteomics screening approach to identify signaling pathways and tyrosine kinase inhibitor targets in highly tumorigenic human lymphoma-like primary cells. We identified several receptor tyrosine kinase pathways and validated SRC family kinases (SFKs) as potential drug targets for targeted selection of small molecule inhibitors. BMS-354825 (dasatinib) and SKI-606 (bosutinib), second and third generation clinical SFK/ABL inhibitors, were found to be potent cytotoxic agents against tumorigenic cells with low toxicity to normal pediatric stem cells. Both SFK inhibitors reduced ERK1/2 and AKT phosphorylation and induced apoptosis. This study supports the adaptation of high-end mass spectrometry techniques for the efficient identification of candidate tyrosine kinases as novel therapeutic targets in primary cancer cell lines.
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Vojvodic Miliana, Hansford M. Loen, Morozova Olena, Blakely M. Kim, Taylor Paul, Fathers E. Kelly, Moffat Jason, Marra Marco, Smith M. Kristen, Moran F. Michael and Kaplan R. David, A Phosphoproteomics Approach to Identify Candidate Kinase Inhibitor Pathway Targets in Lymphoma-Like Primary Cell Lines, Current Drug Discovery Technologies 2013; 10 (4) . https://dx.doi.org/10.2174/15701638113109990001
DOI https://dx.doi.org/10.2174/15701638113109990001 |
Print ISSN 1570-1638 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6220 |
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