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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.

Author information

1
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA, 92307.
2
Pfizer Worldwide Research and Development, 200 Cambridge Park Drive, Cambridge, MA 02140.
3
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340.
4
Pfizer Worldwide Research and Development, 10770 Science Park Drive, San Diego, CA 92121.
5
Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810.
#
Contributed equally

Abstract

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.

PMID:
25038787
PMCID:
PMC4138289
DOI:
10.1038/nchembio.1582
[Indexed for MEDLINE]
Free PMC Article

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