The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.
Prolonged and tunable residence time using reversible covalent kinase inhibitors
Open accessAbstract
Drugs with prolonged, on-target residence time often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here, we demonstrate progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Utilizing an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrate biochemical residence times spanning from minutes to 7 days. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK more than 18 hours after clearance from the circulation. The inverted cyanoacrylamide strategy was further utilized to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating generalizability of the approach. Targeting noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates “residence time by design”, the ability to modulate and improve the duration of target engagement in vivo.
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Features and development of Coot
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Phaser crystallographic software
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MolProbity : all-atom structure validation for macromolecular crystallography
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Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia
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Self-citation
Cited by
Kinase inhibitors: the road ahead
Ferguson, F. M., & Gray, N. S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.21 · Cited by 1,009
Advances in covalent drug discovery
Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823
The drug–target residence time model: a 10-year retrospective
Copeland, R. A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.18 · Cited by 722
A Perspective on the Kinetics of Covalent and Irreversible Inhibition
Strelow, J. M. (2017) · SLAS Discovery · doi:10.1177/1087057116671509 · Cited by 392
Biophysics in drug discovery: impact, challenges and opportunities
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Metadata
- Authors
- Bradshaw, J. M., McFarland, J. M., Paavilainen, V. O., Bisconte, A., Tam, D., Phan, V. T., Romanov, S., Finkle, D., Shu, J., Patel, V., Ton, T., Li, X., Loughhead, D. G., Nunn, P. A., Karr, D. E., Gerritsen, M. E., Funk, J. O., Owens, T. D., Verner, E., Brameld, K. A., Hill, R. J., Goldstein, D. M., & Taunton, J.
- Venue
- Nature Chemical Biology
- Published
- 2015-05-25
- Volume
- 11
- Issue
- 7
- Pages
- 525-531
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W1526377515
- Cited by
- 422
- References
- 55
- FWCI
- 17.23
- Type
- journal article
- Language
- en
- Open access
- green
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- Bradshaw, J. M., McFarland, J. M., Paavilainen, V. O., Bisconte, A., Tam, D., Phan, V. T., Romanov, S., Finkle, D., Shu, J., Patel, V., Ton, T., Li, X., Loughhead, D. G., Nunn, P. A., Karr, D. E., Gerritsen, M. E., Funk, J. O., Owens, T. D., Verner, E., . . . Taunton, J. (2015). Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nature Chemical Biology. https://doi.org/10.1038/nchembio.1817
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
