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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Several potent BTK PROTACs aimed at targeting mutant BTK in ibrutinib-resistant B cell malignancies with improved cellular activities and in vivo potencies were reported.
“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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- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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