Please use this identifier to cite or link to this item:
|Title:||Cell-based proteome profiling of potential Dasatinib targets by use of affinity-based probes||Authors:||Shi, H.
|Issue Date:||15-Feb-2012||Citation:||Shi, H., Zhang, C.-J., Chen, G.Y.J., Yao, S.Q. (2012-02-15). Cell-based proteome profiling of potential Dasatinib targets by use of affinity-based probes. Journal of the American Chemical Society 134 (6) : 3001-3014. ScholarBank@NUS Repository. https://doi.org/10.1021/ja208518u||Abstract:||Protein kinases (PKs) play an important role in the development and progression of cancer by regulating cell growth, survival, invasion, metastasis, and angiogenesis. Dasatinib (BMS-354825), a dual Src/Abl inhibitor, is a promising therapeutic agent with oral bioavailability. It has been used for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). Most kinase inhibitors, including Dasatinib, inhibit multiple cellular targets and do not possess exquisite cellular specificity. Recent efforts in kinase research thus focus on the development of large-scale, proteome-wide chemical profiling methods capable of rapid identification of potential cellular (on- and off-) targets of kinase inhibitors. Most existing approaches, however, are still problematic and in many cases not compatible with live-cell studies. In this work, we have successfully developed a cell-permeable kinase probe (DA-2) capable of proteome-wide profiling of potential cellular targets of Dasatinib. In this way, highly regulated, compartmentalized kinase-drug interactions were maintained. By comparing results obtained from different proteomic setups (live cells, cell lysates, and immobilized affinity matrix), we found DA-2 was able to identify significantly more putative kinase targets. In addition to Abl and Src family tyrosine kinases, a number of previously unknown Dasatinib targets have been identified, including several serine/threonine kinases (PCTK3, STK25, eIF-2A, PIM-3, PKA C-α, and PKN2). They were further validated by pull-down/immunoblotting experiments as well as kinase inhibition assays. Further studies are needed to better understand the exact relevance of Dasatinib and its pharmacological effects in relation to these newly identified cellular targets. The approach developed herein should be amenable to the study of many of the existing reversible drugs/drug candidates. © 2012 American Chemical Society.||Source Title:||Journal of the American Chemical Society||URI:||http://scholarbank.nus.edu.sg/handle/10635/75709||ISSN:||00027863||DOI:||10.1021/ja208518u|
|Appears in Collections:||Staff Publications|
Show full item record
Files in This Item:
There are no files associated with this item.
checked on Jan 22, 2020
WEB OF SCIENCETM
checked on Jan 22, 2020
checked on Dec 29, 2019
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.