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Tinkering outside the kinase ATP box: allosteric (type IV) and bivalent (type V) inhibitors of protein kinases

Kurt J Cox

Department of Chemistry & Biochemistry, University of Arizona, 1306 E. University Blvd, Tucson, AZ 85721, USA

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Carolyn D Shomin

Department of Chemistry & Biochemistry, University of Arizona, 1306 E. University Blvd, Tucson, AZ 85721, USA

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Indraneel Ghosh

† Author for correspondence

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Email the corresponding author at ghosh@email.arizona.edu

Published Online:23 Dec 2010https://doi.org/10.4155/fmc.10.272

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Abstract

Many members of the protein kinase family have emerged as key targets for pharmacological intervention, most notably in cancer. However, the high sequence and structural homology shared by the more than 500 human protein kinases renders it exceedingly difficult to develop selective inhibitors. Most, if not all, existing inhibitors target multiple protein kinases. Current paradigm suggests that an inhibitor that targets multiple kinases and displays polypharmacology is not only acceptable but also often desirable as a therapeutic agent. However, as we move toward personalized medicine the currently acceptable promiscuity is likely to pose significant hurdles in terms of their therapeutic index, especially for diseases that necessitate long-term drug administration. Moreover, selective inhibitors are the only pharmacologically relevant route toward reagents for the dissection of complex signal transduction pathways. This article provides an overview of recent developments in the design of kinase inhibitors that display increasing selectivity by targeting regions outside the highly conserved ATP-binding pocket. These new approaches may pave the way to potentially new avenues for drug discovery while providing valuable tools for studying signal transduction.

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Published online 23 December 2010

Published in print January 2011

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Acknowledgements

We thank members of the Ghosh laboratory for helpful discussions.

Financial & competing interests disclosure

We thank the NIH (R21CA141974) and the NSF (CHE-0548264) for partial support. Kurt J Cox was supported by a an American Chemical Society SURF Award and Carolyn D Shomin was supported by an NIH graduate fellowship The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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