The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Target engagement and drug residence time can be observed in living cells with BRET
Open accessAbstract
The therapeutic action of drugs is predicated on their physical engagement with cellular targets. Here we describe a broadly applicable method using bioluminescence resonance energy transfer (BRET) to reveal the binding characteristics of a drug with selected targets within intact cells. Cell-permeable fluorescent tracers are used in a competitive binding format to quantify drug engagement with the target proteins fused to Nanoluc luciferase. The approach enabled us to profile isozyme-specific engagement and binding kinetics for a panel of histone deacetylase (HDAC) inhibitors. Our analysis was directed particularly to the clinically approved prodrug FK228 (Istodax/Romidepsin) because of its unique and largely unexplained mechanism of sustained intracellular action. Analysis of the binding kinetics by BRET revealed remarkably long intracellular residence times for FK228 at HDAC1, explaining the protracted intracellular behaviour of this prodrug. Our results demonstrate a novel application of BRET for assessing target engagement within the complex milieu of the intracellular environment.
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Cites
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A quantitative analysis of kinase inhibitor selectivity
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Comprehensive analysis of kinase inhibitor selectivity
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Drug-target residence time and its implications for lead optimization
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Tracking cancer drugs in living cells by thermal profiling of the proteome
Savitski, M. M., Reinhard, F. B. M., Franken, H., Werner, T., Savitski, M. F., Eberhard, D., Molina, D. M., Jafari, R., Dovega, R. B., Klaeger, S., et al. (2014) · Science · doi:10.1126/science.1255784 · Cited by 1,187
HDAC family: What are the cancer relevant targets?
Witt, O., Deubzer, H. E., Milde, T., & Oehme, I. (2009) · Cancer Letters · doi:10.1016/j.canlet.2008.08.016 · Cited by 1,069
Chemical phylogenetics of histone deacetylases
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Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes
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Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining
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Cited by
Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight
Ho, T. C. S., Chan, A. H. Y., & Ganesan, A. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00830 · Cited by 795
NanoLuc: A Small Luciferase Is Brightening Up the Field of Bioluminescence
England, C. G., Ehlerding, E. B., & Cai, W. (2016) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.6b00112 · Cited by 591
Quantitative Live-Cell Kinetic Degradation and Mechanistic Profiling of PROTAC Mode of Action
Riching, K. M., Mahan, S., Corona, C. R., McDougall, M., Vasta, J. D., Robers, M. B., Urh, M., & Daniels, D. L. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.8b00692 · Cited by 304
Self-citationThermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat
Becher, I., Werner, T., Doce, C., Zaal, E. A., Tögel, I., Khan, C. A., Rueger, A., Muelbaier, M., Salzer, E., Berkers, C. R., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2185 · Cited by 251
Yang, S.-S., Zhang, R., Wang, G., & Zhang, Y.-F. (2017) · Translational Neurodegeneration · doi:10.1186/s40035-017-0089-1 · Cited by 163
Metadata
- Authors
- Robers, M. B., Dart, M. L., Woodroofe, C. C., Zimprich, C. A., Kirkland, T. A., Machleidt, T., Kupcho, K. R., Levin, S., Hartnett, J. R., Zimmerman, K., Niles, A. L., Ohana, R. F., Daniels, D. L., Slater, M., Wood, M. G., Cong, M., Cheng, Y.-Q., & Wood, K. V.
- Venue
- Nature Communications
- Published
- 2015-12-03
- Volume
- 6
- Issue
- 1
- Pages
- 10091-10091
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2254560754
- Cited by
- 274
- References
- 10
- FWCI
- 9.52
- Type
- journal article
- Language
- en
- Open access
- gold
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