PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding

Tinworth, Christopher P. and Lithgow, Hannah and Dittus, Lars and Bassi, Zuni I. and Hughes, Sophie E. and Muelbaier, Marcel and Dai, Han and Smith, Ian E. D. and Kerr, William J. and Burley, Glenn A. and Bantscheff, Marcus and Harling, John D. (2019) PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding. ACS Chemical Biology, 14 (3). pp. 342-347. ISSN 1554-8937 (https://doi.org/10.1021/acschembio.8b01094)

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Abstract

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.

ORCID iDs

Tinworth, Christopher P. ORCID logoORCID: https://orcid.org/0000-0002-2756-707X, Lithgow, Hannah ORCID logoORCID: https://orcid.org/0000-0002-5115-2296, Dittus, Lars, Bassi, Zuni I., Hughes, Sophie E., Muelbaier, Marcel, Dai, Han, Smith, Ian E. D., Kerr, William J. ORCID logoORCID: https://orcid.org/0000-0002-1332-785X, Burley, Glenn A., Bantscheff, Marcus and Harling, John D.;
  • Item type:Article
    ID code:67192
    Dates:
    Date
    Event
    15 March 2019
    Published
    26 February 2019
    Published Online
    25 February 2019
    Accepted
    Keywords:PROTAC, drug discovery, cellular degradation, protein degradation, E3 ubiquitin-protein ligases, tyrosine kinase, Chemistry, Biochemistry, Molecular Medicine
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Technology and Innovation Centre > Bionanotechnology
    Depositing user: Pure Administrator
    Date deposited:06 Mar 2019 14:42
    Last modified:20 Mar 2023 20:37
    URI:https://strathprints.strath.ac.uk/id/eprint/67192
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