The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
A conserved water-mediated hydrogen bond network defines bosutinib's kinase selectivity
Open accessAbstract
Kinase inhibitors are important cancer drugs, but they tend to display limited target specificity, and their target profiles are often challenging to rationalize in terms of molecular mechanism. Here we report that the clinical kinase inhibitor bosutinib recognizes its kinase targets by engaging a pair of conserved structured water molecules in the active site, and that many other kinase inhibitors share a similar recognition mechanism. Using the nitrile group of bosutinib as an infrared probe, we show that the gatekeeper residue and one other position in the ATP-binding site control access of the drug to the structured water molecules, and that the amino acids found at these positions account for the kinome-wide target spectrum of the drug. Our work highlights the importance of structured water molecules for inhibitor recognition, reveals a new role for the kinase gatekeeper, and showcases an effective approach for elucidating the molecular origins of selectivity patterns.
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Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors
Demetri, G. D., von Mehren, M., Blanke, C. D., Van den Abbeele, A. D., Eisenberg, B., Roberts, P. J., Heinrich, M. C., Tuveson, D. A., Singer, S., Janicek, M., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa020461 · Cited by 4,389
Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification
Gorre, M. E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P. N., & Sawyers, C. L. (2001) · Science · doi:10.1126/science.1062538 · Cited by 3,104
Comprehensive analysis of kinase inhibitor selectivity
Davis, M. I., Hunt, J. P., Herrgard, S., Ciceri, P., Wodicka, L. M., Pallares, G., Hocker, M., Treiber, D. K., & Zarrinkar, P. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1990 · Cited by 2,409
Cited by
FDA-approved small-molecule kinase inhibitors
Wu, P., Nielsen, T. E., & Clausen, M. H. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.04.005 · Cited by 1,013
Roskoski, R. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2015.10.021 · Cited by 886
Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors
Roskoski, R. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.01.003 · Cited by 607
Verkhivker, G. M., Agajanian, S., Hu, G., & Tao, P. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00136 · Cited by 76
Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drugs
Heinzlmeir, S., Kudlinzki, D., Sreeramulu, S., Klaeger, S., Gande, S. L., Linhard, V., Wilhelm, M., Qiao, H., Helm, D., Ruprecht, B., et al. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00709 · Cited by 56
Metadata
- Authors
- Levinson, N. M., & Boxer, S. G.
- Venue
- Nature Chemical Biology
- Published
- 2013-12-01
- Volume
- 10
- Issue
- 2
- Pages
- 127-132
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W1965009739
- Cited by
- 171
- References
- 3
- FWCI
- 11.33
- Type
- journal article
- Language
- en
- Open access
- green
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