Journal
ACS CHEMICAL BIOLOGY
Volume 14, Issue 3, Pages 342-347Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.8b01094
Keywords
-
Categories
Funding
- GlaxoSmithKline
- University of Strathclyde
- EPSRC [EP/S035990/1] Funding Source: UKRI
Ask authors/readers for more resources
The impact of covalent binding on PROTAC-mediated degradation of BTK was investigated through the preparation of both covalent binding and reversible binding PROTACs derived from the covalent BTK inhibitor ibrutinib. It was determined that a covalent binding PROTAC inhibited BTK degradation despite evidence of target engagement, while BTK degradation was observed with a reversible binding PROTAC. These observations were consistently found when PROTACs that were able to recruit either IAP or cereblon E3 ligases were employed. Proteomics analysis determined that the use of a covalently bound PROTAC did not result in the degradation of covalently bound targets, while degradation was observed for some reversibly bound targets. This observation highlights the importance of catalysis for successful PROTAC-mediated degradation and highlights a potential caveat for the use of covalent target binders in PROTAC design.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available