NDLI: Staurosporine-derived inhibitors broaden the scope of analog-sensitive kinase technology

Content Provider	PubMed Central
Author	Lopez, Michael S. Choy, Jonathan W. Peters, Ulf Sos, Martin L. Morgan, David O. Shokat, Kevan M.
Abstract	Analog-sensitive (AS) kinase technology is a powerful approach for studying phospho-signaling pathways in diverse organisms and physiological processes. The key feature of this technique is that a kinase-of-interest can be mutated to sensitize it to inhibitor analogs that do not target wild-type (WT) kinases. In theory, this enables specific inhibition of any kinase in cells and in mouse models of human disease. Typically these inhibitors are identified from a small library of molecules based on the pyrazolopyrimidine (PP) scaffold. However, we recently identified a subset of native human kinases, including the Ephrin A kinase family, that are sensitive to commonly used PP inhibitors. In an effort to develop a bioorthogonal AS-kinase inhibitor and to extend this technique to PP-sensitive kinases we sought an alternative inhibitor scaffold. Here we report the structure-based design of synthetically tractable, potent, and extremely selective AS-kinase inhibitors based on the natural product staurosporine. We demonstrate that these molecules, termed staralogs, potently target AS kinases in cells and we employ X-ray crystallography to elucidate their mechanism of efficacy. Finally, we demonstrate that staralogs target AS mutants of PP-sensitive kinases at concentrations where there is little to no inhibition of native human kinases. Thus, staralogs represent a new class of AS-kinase inhibitors and a core component of the chemical genetic tool kit for probing kinase-signaling pathways.
Related Links	http://dx.doi.org/10.1021/ja408704u
Ending Page	18159
Page Count	7
Starting Page	18153
File Format	PDF
ISSN	00027863
e-ISSN	15205126
Journal	Journal of the American Chemical Society
Issue Number	48
Volume Number	135
Language	English
Publisher Date	2013-12-04
Access Restriction	Open
Subject Keyword	Colloid and Surface Chemistry Biochemistry Chemistry(all) Catalysis Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Chemistry Colloid and Surface Chemistry Biochemistry Catalysis

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