The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
Efficient targeted degradation via reversible and irreversible covalent PROTACs
Open accessAbstract
PROteolysis Targeting Chimeras (PROTACs) represent an exciting inhibitory modality with many advantages, including sub-stoichiometric degradation of targets. Their scope, though, is still limited to-date by the requirement for a sufficiently potent target binder. A solution that proved useful in tackling challenging targets is the use of electrophiles to allow irreversible binding to the target. However, such binding will negate the catalytic nature of PROTACs. Reversible covalent PROTACs offer the best of both worlds. They possess the potency and selectivity associated with the formation of the covalent bond, while being able to dissociate and regenerate once the protein target is degraded. Using Bruton’s tyrosine kinase (BTK) as a clinically relevant model system, we present a proof-of concept for the first in class cyanoacrylamide reversible covalent PROTACs. We show efficient degradation with reversible covalent PROTACs, as well as their non-covalent and irreversible counterparts. The latter are amongst the most efficient PROTACs reported for BTK. They display single digit nM DC50, full degradation within 2-4 hours, proteome wide selectivity and show ~10-fold better inhibition of B cell activation than Ibrutinib. These examples refute the notion that covalent binders are not suitable as the basis for PROTACs, and may pave the way for the design of covalent PROTACs for a wide variety of challenging targets.
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“Subsequently, several potent BTK PROTACs aimed at targeting mutant BTK in ibrutinib-resistant B cell malignancies with improved cellular activities and possessing in vivo potencies were reported by different groups [7, 44, 118–120].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [120]
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Honigberg, L. A., Smith, A. M., Sirisawad, M., Verner, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D. H., Miller, R. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004594107 · Cited by 1,561
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356
Structural basis of PROTAC cooperative recognition for selective protein degradation
Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2329 · Cited by 1,242
Small molecules, big targets: drug discovery faces the protein–protein interaction challenge
Scott, D. E., Bayly, A. R., Abell, C., & Skidmore, J. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.29 · Cited by 1,137
Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality
Arkin, M. R., Tang, Y., & Wells, J. A. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.09.001 · Cited by 1,065
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
Zengerle, M., Chan, K.-H., & Ciulli, A. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00216 · Cited by 1,056
Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.010 · Cited by 923
PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future
Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 830
Role of Bruton’s tyrosine kinase in B cells and malignancies
Pal Singh, S., Dammeijer, F., & Hendriks, R. W. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0779-z · Cited by 726
Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase
Pan, Z., Scheerens, H., Li, S., Schultz, B. E., Sprengeler, P. A., Burrill, L. C., Mendonca, R. V., Sweeney, M. D., Scott, K. C. K., Grothaus, P. G., et al. (2006) · ChemMedChem · doi:10.1002/cmdc.200600221 · Cited by 690
Cited by
Sorted by citations
Advancing targeted protein degradation for cancer therapy
Dale, B., Cheng, M., Park, K., Kanıskan, H. Ü., Xiong, Y., & Jin, J. J. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00365-x · Cited by 697
PROTACs: An Emerging Therapeutic Modality in Precision Medicine
Nalawansha, D. A., & Crews, C. M. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.07.020 · Cited by 523
Current strategies for the design of PROTAC linkers: a critical review
Troup, R. I., Fallan, C., & Baud, M. G. J. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00018 · Cited by 424
Proteolysis-targeting chimeras (PROTACs) in cancer therapy
Li, X., Pu, W., Zheng, Q., Ai, M., Chen, S., & Peng, Y. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01434-3 · Cited by 389
Target and tissue selectivity of PROTAC degraders
Guenette, R. G., Yang, S. W., Min, J., Pei, B., & Potts, P. R. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00200k · Cited by 324
Metadata
- Authors
- Gabizon, R., Shraga, A., Gehrtz, P., Livnah, E., Gurwicz, N., Avram, L., Unger, T., Albeck, S., Shulman, Z., & London, N.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- London, Nir
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-01-08
- Volume
- 142
- Issue
- 27
- Pages
- 11734-11742
- ISSN
- 0002-7863 (ISSN-L)
- PMC
- PMC7349657
- OpenAlex
- W3021210206
- Cited by
- 213
- References
- 39
- Citations by year
- 2026: 29 · 2025: 30 · 2024: 34 · 2023: 26 · 2022: 42 · 2021: 34 · 2020: 18
- FWCI
- 10.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of the American Chemical Society (publishedVersion, cc-by)
- ChemRxiv (acceptedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Israel Cancer Research Fund
- Weizmann Institute of Science
- Ministry of Aliyah and Immigrant Absorption
- Israel Cancer Association
- Israel Science Foundation (2462/19, 1707/19)
- Tel Aviv University
- Ministry of Science and Technology, Israel (3-14763)
- Rising Tide Foundation
- Helen and Martin Kimmel Center for Molecular Design, Weizmann Institute of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Keywords
- PROTACs, targeted protein degradation, Bruton's tyrosine kinase, chronic lymphocytic leukemia, ibrutinib
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