The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Design of Reversible, Cysteine-Targeted Michael Acceptors Guided by Kinetic and Computational Analysis
Open accessAbstract
Electrophilic probes that covalently modify a cysteine thiol often show enhanced pharmacological potency and selectivity. Although reversible Michael acceptors have been reported, the structural requirements for reversibility are poorly understood. Here, we report a novel class of acrylonitrile-based Michael acceptors, activated by aryl or heteroaryl electron-withdrawing groups. We demonstrate that thiol adducts of these acrylonitriles undergo β-elimination at rates that span more than 3 orders of magnitude. These rates correlate inversely with the computed proton affinity of the corresponding carbanions, enabling the intrinsic reversibility of the thiol-Michael reaction to be tuned in a predictable manner. We apply these principles to the design of new reversible covalent kinase inhibitors with improved properties. A cocrystal structure of one such inhibitor reveals specific noncovalent interactions between the 1,2,4-triazole activating group and the kinase. Our experimental and computational study enables the design of new Michael acceptors, expanding the palette of reversible, cysteine-targeted electrophiles.
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Sequist, L. V., Yang, J. C.-H., Yamamoto, N., O'Byrne, K., Hirsh, V., Mok, T., Geater, S. L., Orlov, S., Tsai, C.-M., Boyer, M., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.2806 · Cited by 3,228
Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia
Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Grant, B., Sharman, J. P., Coleman, M., Wierda, W. G., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1215637 · Cited by 2,270
The resurgence of covalent drugs
Singh, J., Petter, R. C., Baillie, T. A., & Whitty, A. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3410 · Cited by 1,873
Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore
Fleming, F. F., Yao, L., Ravikumar, P. C., Funk, L., & Shook, B. C. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm100762r · Cited by 1,754
Drug-target residence time and its implications for lead optimization
Copeland, R. A., Pompliano, D. L., & Meek, T. D. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2082 · Cited by 1,464
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Developing Irreversible Inhibitors of the Protein Kinase Cysteinome
Liu, Q., Sabnis, Y., Zhao, Z., Zhang, T., Buhrlage, S. J., Jones, L. H., & Gray, N. S. (2013) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.12.006 · Cited by 652
Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles
Serafimova, I. M., Pufall, M. A., Krishnan, S., Duda, K., Cohen, M. S., Maglathlin, R. L., McFarland, J. M., Miller, R. M., Frödin, M., & Taunton, J. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.925 · Cited by 493
Self-citationThe discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K
Gauthier, J. Y., Chauret, N., Cromlish, W., Desmarais, S., Duong, L. T., Falgueyret, J.-P., Kimmel, D. B., Lamontagne, S., Léger, S., LeRiche, T., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2007.12.047 · Cited by 477
Managing the challenge of chemically reactive metabolites in drug development
Park, B. K., Boobis, A., Clarke, S., Goldring, C. E. P., Jones, D., Kenna, J. G., Lambert, C., Laverty, H. G., Naisbitt, D. J., Nelson, S., et al. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3408 · Cited by 462
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
Jackson, P. A., Widen, J. C., Harki, D. A., & Brummond, K. M. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00788 · Cited by 588
Targeted Covalent Inhibitors for Drug Design
Baillie, T. A. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201601091 · Cited by 578
Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening
Resnick, E., Bradley, A., Gan, J., Douangamath, A., Krojer, T., Sethi, R., Geurink, P. P., Aimon, A., Amitai, G., Bellini, D., et al. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b02822 · Cited by 335
Flanagan, M. E., Abramite, J. A., Anderson, D. P., Aulabaugh, A., Dahal, U. P., Gilbert, A. M., Li, C., Montgomery, J., Oppenheimer, S. R., Ryder, T., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501412a · Cited by 320
Metadata
- Authors
- Krishnan, S., Miller, R. M., Tian, B., Mullins, R. D., Jacobson, M. P., & Taunton, J.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-09-02
- Volume
- 136
- Issue
- 36
- Pages
- 12624-12630
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2048072131
- Cited by
- 260
- References
- 30
- FWCI
- 8.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Krishnan, S., Miller, R. M., Tian, B., Mullins, R. D., Jacobson, M. P., & Taunton, J. (2014). Design of Reversible, Cysteine-Targeted Michael Acceptors Guided by Kinetic and Computational Analysis. Journal of the American Chemical Society. https://doi.org/10.1021/ja505194w
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
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.
