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

Christopher P. Tinworth, Hannah Lithgow, Lars Dittus, Zuni I. Bassi, Sophie E. Hughes, Marcel Muelbaier, Han Dai, Ian E. D. Smith, William J. Kerr, Glenn A. Burley, Marcus Bantscheff, John D. Harling

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

LanguageEnglish
Pages342-347
Number of pages6
JournalACS Chemical Biology
Volume14
Issue number3
Early online date26 Feb 2019
DOIs
Publication statusPublished - 15 Mar 2019

Fingerprint

Ubiquitin-Protein Ligases
Catalysis
Proteomics
Degradation
Binders
PCI 32765
Agammaglobulinaemia tyrosine kinase

Keywords

  • PROTAC
  • drug discovery
  • cellular degradation
  • protein degradation
  • E3 ubiquitin-protein ligases
  • tyrosine kinase

Cite this

Tinworth, C. P., Lithgow, H., Dittus, L., Bassi, Z. I., Hughes, S. E., Muelbaier, M., ... Harling, J. D. (2019). PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding. ACS Chemical Biology, 14(3), 342-347. https://doi.org/10.1021/acschembio.8b01094
Tinworth, Christopher P. ; Lithgow, Hannah ; Dittus, Lars ; Bassi, Zuni I. ; Hughes, Sophie E. ; Muelbaier, Marcel ; Dai, Han ; Smith, Ian E. D. ; Kerr, William J. ; Burley, Glenn A. ; Bantscheff, Marcus ; Harling, John D. / PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding. In: ACS Chemical Biology. 2019 ; Vol. 14, No. 3. pp. 342-347.
@article{50644ea5ec3742449e60ff2b71cf4f7a,
title = "PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding",
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.",
keywords = "PROTAC, drug discovery, cellular degradation, protein degradation, E3 ubiquitin-protein ligases, tyrosine kinase",
author = "Tinworth, {Christopher P.} and Hannah Lithgow and Lars Dittus and Bassi, {Zuni I.} and Hughes, {Sophie E.} and Marcel Muelbaier and Han Dai and Smith, {Ian E. D.} and Kerr, {William J.} and Burley, {Glenn A.} and Marcus Bantscheff and Harling, {John D.}",
year = "2019",
month = "3",
day = "15",
doi = "10.1021/acschembio.8b01094",
language = "English",
volume = "14",
pages = "342--347",
journal = "ACS Chemical Biology",
issn = "1554-8929",
publisher = "American Chemical Society",
number = "3",

}

Tinworth, CP, Lithgow, H, Dittus, L, Bassi, ZI, Hughes, SE, Muelbaier, M, Dai, H, Smith, IED, Kerr, WJ, Burley, GA, Bantscheff, M & Harling, JD 2019, 'PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding' ACS Chemical Biology, vol. 14, no. 3, pp. 342-347. https://doi.org/10.1021/acschembio.8b01094

PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding. / Tinworth, Christopher P.; Lithgow, Hannah; Dittus, Lars ; Bassi, Zuni I.; Hughes, Sophie E.; Muelbaier, Marcel; Dai, Han; Smith, Ian E. D.; Kerr, William J.; Burley, Glenn A.; Bantscheff, Marcus; Harling, John D.

In: ACS Chemical Biology, Vol. 14, No. 3, 15.03.2019, p. 342-347.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding

AU - Tinworth, Christopher P.

AU - Lithgow, Hannah

AU - Dittus, Lars

AU - Bassi, Zuni I.

AU - Hughes, Sophie E.

AU - Muelbaier, Marcel

AU - Dai, Han

AU - Smith, Ian E. D.

AU - Kerr, William J.

AU - Burley, Glenn A.

AU - Bantscheff, Marcus

AU - Harling, John D.

PY - 2019/3/15

Y1 - 2019/3/15

N2 - 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.

AB - 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.

KW - PROTAC

KW - drug discovery

KW - cellular degradation

KW - protein degradation

KW - E3 ubiquitin-protein ligases

KW - tyrosine kinase

U2 - 10.1021/acschembio.8b01094

DO - 10.1021/acschembio.8b01094

M3 - Article

VL - 14

SP - 342

EP - 347

JO - ACS Chemical Biology

T2 - ACS Chemical Biology

JF - ACS Chemical Biology

SN - 1554-8929

IS - 3

ER -