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

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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:09 Dec 2021 01:51
      URI:https://strathprints.strath.ac.uk/id/eprint/67192
    CORE (COnnecting REpositories)