2. Academic Validation
  3. PROTAC-Mediated Degradation of Bruton's Tyrosine Kinase Is Inhibited by Covalent Binding

PROTAC-Mediated Degradation of Bruton's Tyrosine Kinase Is Inhibited by Covalent Binding

  • ACS Chem Biol. 2019 Mar 15;14(3):342-347. doi: 10.1021/acschembio.8b01094.
Christopher P Tinworth 1 2,  Hannah Lithgow 1 2,  Lars Dittus 3,  Zuni I Bassi 1,  Sophie E Hughes 1,  Marcel Muelbaier 3,  Han Dai 4,  Ian E D Smith 1,  William J Kerr 2,  Glenn A Burley 2,  Marcus Bantscheff 3,  John D Harling 1
Affiliations

Affiliations

  • 1 GSK Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.
  • 2 Department of Pure and Applied Chemistry, WestCHEM , University of Strathclyde , 295 Cathedral Street , Glasgow G1 1XL , U.K.
  • 3 Cellzome GmbH, GlaxoSmithKline , Meyerhofstrasse 1 , D-69117 Heidelberg , Germany.
  • 4 GlaxoSmithKline , 1250 South Collegeville Road , Collegeville , Pennsylvania 19426 , United States.
PMID: 30807093 DOI: 10.1021/acschembio.8b01094
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.

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