PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding
| Autor: | John D. Harling, Hannah Lithgow, William J. Kerr, Marcus Bantscheff, Zuni I. Bassi, Marcel Muelbaier, Han Dai, Ian Edward David Smith, Christopher P. Tinworth, Sophie E. Hughes, Lars Dittus, Glenn A. Burley |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Ubiquitin-Protein Ligases Plasma protein binding Protein degradation 01 natural sciences Biochemistry Inhibitor of Apoptosis Proteins 03 medical and health sciences chemistry.chemical_compound Piperidines hemic and lymphatic diseases Agammaglobulinaemia Tyrosine Kinase Bruton's tyrosine kinase QD Protein Kinase Inhibitors biology 010405 organic chemistry Drug discovery Adenine Cereblon General Medicine 0104 chemical sciences Pyrimidines 030104 developmental biology chemistry Covalent bond Ibrutinib Proteolysis biology.protein Biophysics Pyrazoles Molecular Medicine Tyrosine kinase Protein Binding |
| ISSN: | 1554-8937 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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