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Efficient Targeted Degradation via Reversible and Irreversible Covalent PROTACs.
Gabizon, Ronen; Shraga, Amit; Gehrtz, Paul; Livnah, Ella; Shorer, Yamit; Gurwicz, Neta; Avram, Liat; Unger, Tamar; Aharoni, Hila; Albeck, Shira; Brandis, Alexander; Shulman, Ziv; Katz, Ben-Zion; Herishanu, Yair; London, Nir.
Affiliation
  • Gabizon R; Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Shraga A; Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Gehrtz P; Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Livnah E; Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Shorer Y; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.
  • Gurwicz N; Department of Immunology, The Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Avram L; Department of Chemical Research Support, The Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Unger T; Structural Proteomics Unit, Department of Life Sciences Core Facilities, The Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Aharoni H; Structural Proteomics Unit, Department of Life Sciences Core Facilities, The Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Albeck S; Structural Proteomics Unit, Department of Life Sciences Core Facilities, The Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Brandis A; Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Shulman Z; Department of Immunology, The Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Katz BZ; Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.
  • Herishanu Y; Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.
  • London N; Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 7610001, Israel.
J Am Chem Soc ; 142(27): 11734-11742, 2020 07 08.
Article in En | MEDLINE | ID: mdl-32369353
ABSTRACT
Proteolysis targeting chimeras (PROTACs) represent an exciting inhibitory modality with many advantages, including substoichiometric 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 potentially 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 show efficient degradation by noncovalent, irreversible covalent, and reversible covalent PROTACs, with <10 nM DC50's and >85% degradation. Our data suggest that part of the degradation by our irreversible covalent PROTACs is driven by reversible binding prior to covalent bond formation, while the reversible covalent PROTACs drive degradation primarily by covalent engagement. The PROTACs showed enhanced inhibition of B cell activation compared to ibrutinib and exhibit potent degradation of BTK in patient-derived primary chronic lymphocytic leukemia cells. The most potent reversible covalent PROTAC, RC-3, exhibited enhanced selectivity toward BTK compared to noncovalent and irreversible covalent PROTACs. These compounds may pave the way for the design of covalent PROTACs for a wide variety of challenging targets.

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: J Am Chem Soc Year: 2020 Document type: Article Affiliation country: Israel

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: J Am Chem Soc Year: 2020 Document type: Article Affiliation country: Israel