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Nat Chem Biol. 2014 Sep;10(9):760-767. doi: 10.1038/nchembio.1582. Epub 2014 Jul 13.

A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors.

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The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA, 92307.
Pfizer Worldwide Research and Development, 200 Cambridge Park Drive, Cambridge, MA 02140.
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340.
Pfizer Worldwide Research and Development, 10770 Science Park Drive, San Diego, CA 92121.
Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810.
Contributed equally


Kinases are principal components of signal transduction pathways and the focus of intense basic and drug discovery research. Irreversible inhibitors that covalently modify non-catalytic cysteines in kinase active sites have emerged as valuable probes and approved drugs. Many protein classes, however, have functional cysteines, and therefore understanding the proteome-wide selectivity of covalent kinase inhibitors is imperative. Here, we accomplish this objective using activity-based protein profiling coupled with quantitative MS to globally map the targets, both specific and nonspecific, of covalent kinase inhibitors in human cells. Many of the specific off-targets represent nonkinase proteins that, notably, have conserved active site cysteines. We define windows of selectivity for covalent kinase inhibitors and show that, when these windows are exceeded, rampant proteome-wide reactivity and kinase target-independent cell death conjointly occur. Our findings, taken together, provide an experimental road map to illuminate opportunities and surmount challenges for the development of covalent kinase inhibitors.

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