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Efficient targeted degradation via reversible and irreversible covalent PROTACs

preprint
submitted on 02.01.2020, 14:43 and posted on 08.01.2020, 20:15 by Ronen Gabizon, Amit Shraga, Paul Gehrtz, Ella Livnah, Neta Gurwicz, Liat Avram, Tamar Unger, Shira Albeck, Ziv Shulman, Nir London

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.

Funding

S.A. is the incumbent of Prof. David Casson Research Fellowship, N.L. is the incumbent of the Alan and Laraine Fischer Career Development Chair; N.L. would like to acknowledge funding from the Israel Science Foundation (grant No. 2462/19), The Rising Tide Foundation, The Israel Cancer Research Fund, the Israeli Ministry of Science. Technology (grant No. 3-14763), and the Moross integrated cancer center. N.L. is also supported by the Helen and Martin Kimmel Center for Molecular Design, Joel and Mady Dukler Fund for Cancer Research, the Estate of Emile Mimran and Virgin JustGiving and the George Schwartzman Fund. R.G. was supported by the state of Israel, ministry of Aliyah, Center for Integration in Science.

History

Email Address of Submitting Author

nir.london@weizmann.ac.il

Institution

The Weizmann Institute of Science

Country

Israel

ORCID For Submitting Author

https://orcid.org/0000-0003-2687-0699

Declaration of Conflict of Interest

no conflict of interest

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