PreprintCited by 221Protein Degradation and InhibitorsChemical Synthesis and AnalysisClick Chemistry and Applications

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Efficient targeted degradation via reversible and irreversible covalent PROTACs

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Gabizon, Ronen, Shraga, Amit, Gehrtz, Paul, Livnah, Ella, Gurwicz, Neta, Avram, Liat, Unger, Tamar, Albeck, Shira, Shulman, Ziv, London, Nir·2020·Journal of the American Chemical Society

DOI 10.26434/chemrxiv.11494398.v1PMC PMC7349657

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Abstract

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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The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy
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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: Gabizon, Ronen
Shraga, Amit
Gurwicz, Neta
Avram, Liat
Unger, Tamar
Albeck, Shira
Shulman, Ziv
London, Nir
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)
DOI: 10.26434/chemrxiv.11494398.v1
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
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
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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Efficient targeted degradation via reversible and irreversible covalent PROTACs

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