Characterization of covalent binding of tyrosine kinase inhibitors to plasma proteins
Abstract
Eight covalent tyrosine kinase inhibitors (TKIs) were investigated to determine the characteristics of their covalent binding to plasma proteins. The data revealed that their covalent binding to plasma proteins is of species difference. In addition to the reports on neratinib and pyrotinib, osimertinib, alflutinib, AST5902, and ibrutinib were confirmed to covalently bind to the Lys-190 of human serum albumin (HSA). Molecular docking was used to simulate the binding mode of TKIs to HSA. The results exhibited the non-covalent interactions between covalent TKIs and HSA, which stabilize the TKIs-HSA complex and explain the selectivity of covalent binding. The t 1/2 values of TKIs that are covalently bound to HSA or human plasma proteins were studied in vitro, and the features highly correlated with the t 1/2 were determined by quantitative calculations and linear modeling. Reversibility of the covalent binding and the factors affecting the process of reversibility were evaluated. In conclusion, acrylamide moiety of covalent TKIs can covalently bind to lysine residue of HSA, most of which were determined to be Lys-190. The covalent binding is of species difference, especially between animal and human. Except for osimertinib, covalent binding between TKIs and HSA are reversible.
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This enhances alflutinib's activity and kinase selectivity while reducing off-target effects, leading to fewer side effects.
“This enhances alflutinib’s activity and kinase selectivity while reducing off-target effects, leading to fewer side effects.146–148”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [147]
Cites
Atomic structure and chemistry of human serum albumin
He, X. M., & Carter, D. C. (1992) · Nature · doi:10.1038/358209a0 · Cited by 3,833 · see citing works
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 · see citing works
Kinase-targeted cancer therapies: progress, challenges and future directions
Bhullar, K. S., Orrego-Lagarón, N., McGowan, E. M., Parmar, I., Jha, A., Hubbard, B. P., & Rupasinghe, H. P. V. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0804-2 · Cited by 1,260 · see citing works
Targeted Covalent Inhibitors for Drug Design
Baillie, T. A. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201601091 · Cited by 578 · see citing works
Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update
Roskoski, R. J. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104609 · Cited by 566 · see citing works
Osimertinib As First-Line Treatment of EGFR Mutation–Positive Advanced Non–Small-Cell Lung Cancer
Ramalingam, S. S., Yang, J. C., Lee, C. K., Kurata, T., Kim, D., John, T., Nogami, N., Ohe, Y., Mann, H., Rukazenkov, Y., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2017.74.7576 · Cited by 554 · see citing works
Kinase mutations in human disease: interpreting genotype–phenotype relationships
Lahiry, P., Torkamani, A., Schork, N. J., & Hegele, R. A. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2707 · Cited by 420 · see citing works
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 · see citing works
The importance of plasma protein binding in drug discovery
Trainor, G. L. (2007) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2.1.51 · Cited by 352 · see citing works
Structure of Human Serum Albumin
Carter, D. C., & He, X. (1990) · Science · doi:10.1126/science.2374930 · Cited by 320 · see citing works
The ins and outs of selective kinase inhibitor development
Müller, S., Chaikuad, A., Gray, N. S., & Knapp, S. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1938 · Cited by 276 · see citing works
Protein kinase signaling networks in cancer
Brognard, J., & Hunter, T. R. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.10.012 · Cited by 241 · see citing works
Pyrotinib: First Global Approval
Blair, H. A. (2018) · Drugs · doi:10.1007/s40265-018-0997-0 · Cited by 206 · see citing works
Neratinib: First Global Approval
Deeks, E. D. (2017) · Drugs · doi:10.1007/s40265-017-0811-4 · Cited by 148 · see citing works
Scheers, E. M., Leclercq, L., de Jong, J., Bode, N., Bockx, M., Laenen, A., Cuyckens, F., Skee, D. M., Murphy, J., Sukbuntherng, J., et al. (2014) · Drug Metabolism and Disposition · doi:10.1124/dmd.114.060061 · Cited by 143 · see citing works
Role of Plasma Lipoproteins in Modifying the Biological Activity of Hydrophobic Drugs
Wasan, K. M., & Cassidy, S. M. (1998) · Journal of Pharmaceutical Sciences · doi:10.1021/js970407a · Cited by 140 · see citing works
Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers
Stopfer, P., Marzin, K., Narjes, H., Gansser, D., Shahidi, M., Uttereuther-Fischer, M., & Ebner, T. (2012) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-011-1803-9 · Cited by 137 · see citing works
Dickinson, P. A., Cantarini, M., Collier, J., Frewer, P., Martin, S. W., Pickup, K., & Ballard, P. G. (2016) · Drug Metabolism and Disposition · doi:10.1124/dmd.115.069203 · Cited by 137 · see citing works
Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of Drug Therapy
Tozer, T. N., & Rowland, M. (2006) · Cited by 106 · see citing works
Species differences in drug plasma protein binding
Colclough, N., Ruston, L., Wood, J. M., & MacFaul, P. A. (2014) · MedChemComm · doi:10.1039/c4md00148f · Cited by 69 · see citing works
Characterization of HKI-272 Covalent Binding to Human Serum Albumin
Wang, J., Li-Chan, X. X., Atherton, J., Deng, L., Espina, R. J., Yu, L., Horwatt, P., Ross, S. A., Lockhead, S., Ahmad, S. S., et al. (2010) · Drug Metabolism and Disposition · doi:10.1124/dmd.110.032292 · Cited by 61 · see citing works
How Reactive are Druggable Cysteines in Protein Kinases?
Awoonor‐Williams, E., & Rowley, C. N. (2018) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.8b00454 · Cited by 57 · see citing works
Meng, J., Liu, X.-Y., Ma, S., Zhang, H., Yu, S.-D., Zhang, Y.-F., Chen, M.-X., Zhu, X.-Y., Liu, Y., Yi, L., et al. (2019) · Acta Pharmacologica Sinica · doi:10.1038/s41401-018-0176-6 · Cited by 41 · see citing works
Self-citationUnderstanding the Interaction Between Human Serum Albumin and Anti-Bacterial/ Anti-Cancer Compounds
Rehman, M. T., & Khan, A. U. (2015) · Current Pharmaceutical Design · doi:10.2174/1381612821666150304161201 · Cited by 40 · see citing works
Ballard, T. E., Dahal, U. P., Bessire, A. J., Schneider, R. P., Geoghegan, K. F., & Vaz, A. D. N. (2015) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.7375 · Cited by 11 · see citing works
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Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans
Meng, J., Zhang, H., Bao, J.-J., Chen, Z.-D., Liu, X.-Y., Zhang, Y.-F., Jiang, Y., Miao, L.-Y., & Zhong, D.-F. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00667-8 · Cited by 23 · see citing works
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Self-citation
- Authors
- Liu, X., Feng, D., Zheng, M., Cui, Y., & Zhong, D.
- Affiliations
- Chinese Academy of Sciences (CN)
- Shanghai University (CN)
- Corresponding author
- Zhong, Dafang
- Venue
- Drug Metabolism and Pharmacokinetics
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 35
- Issue
- 5
- Pages
- 456-465
- ISSN
- 1347-4367 (ISSN-L)
- OpenAlex
- W3044159365
- Cited by
- 32
- References
- 25
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 7 · 2023: 4 · 2022: 3 · 2021: 6
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Pharmacokinetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81521005)
- Chinese Academy of Sciences (XDA12050306)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- tyrosine kinase inhibitors, covalent binding, plasma proteins, human serum albumin, species differences, half-life, osimertinib, neratinib, pyrotinib, ibrutinib, molecular docking
- MeSH terms
- Serum Albumin, Human, Acrylamides, Adenine, Aminoquinolines, Aniline Compounds, Animals, Haplorhini, Binding Sites, Dogs, Humans, Indoles, Lysine, Piperidines, Pyridines, Pyrimidines, Quinolines, Rabbits, Molecular Structure, Protein Kinase Inhibitors, Mice, Rats, Molecular Docking Simulation
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