The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors
Open accessAbstract
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, possess 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 mass spectrometry to globally map the targets, both specific and non-specific, of covalent kinase inhibitors in human cells. Many of the specific off-targets represent non-kinase proteins that, interestingly, possess 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 roadmap to illuminate opportunities and surmount challenges for the development of covalent kinase inhibitors.
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Functional and quantitative proteomics using SILAC
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Strategies for Discovering and Derisking Covalent, Irreversible Enzyme Inhibitors
Johnson, D. S., Weerapana, E., & Cravatt, B. F. (2010) · Future Medicinal Chemistry · doi:10.4155/fmc.10.21 · Cited by 387
Self-citationIrreversible Protein Kinase Inhibitors: Balancing the Benefits and Risks
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DAGLβ inhibition perturbs a lipid network involved in macrophage inflammatory responses
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Backus, K. M., Correia, B. E., Lum, K. M., Forli, S., Horning, B. D., González-Páez, G. E., Chatterjee, S., Lanning, B. R., Teijaro, J. R., Olson, A. J., et al. (2016) · Nature · doi:10.1038/nature18002 · Cited by 940
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Metadata
- Authors
- Lanning, B. R., Whitby, L. R., Dix, M. M., Douhan, J., Gilbert, A. M., Hett, E. C., Johnson, T. O., Joslyn, C., Kath, J. C., Niessen, S., Roberts, L. R., Schnute, M. E., Wang, C., Hulce, J. J., Wei, B., Whiteley, L. O., Hayward, M. M., & Cravatt, B. F.
- Venue
- Nature Chemical Biology
- Published
- 2014-07-13
- Volume
- 10
- Issue
- 9
- Pages
- 760-767
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2093859044
- Cited by
- 359
- References
- 7
- FWCI
- 13.33
- Type
- journal article
- Language
- en
- Open access
- green
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- Lanning, B. R., Whitby, L. R., Dix, M. M., Douhan, J., Gilbert, A. M., Hett, E. C., Johnson, T. O., Joslyn, C., Kath, J. C., Niessen, S., Roberts, L. R., Schnute, M. E., Wang, C., Hulce, J. J., Wei, B., Whiteley, L. O., Hayward, M. M., & Cravatt, B. F. (2014). A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors. Nature Chemical Biology. https://doi.org/10.1038/nchembio.1582
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