One-Pot Synthesis of Cereblon Proteolysis Targeting Chimeras via Photoinduced C(sp2)-C(sp3) Cross Coupling and Amide Formation for Proteolysis Targeting Chimera Library Synthesis

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Christine M Arndt
  • Jacqueline Bitai
  • Jessica Brunner
  • Till Opatz
  • Paola Martinelli
  • Andreas Gollner
  • Kevin R Sokol
  • Matthias Krumb
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:001134050600001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1021/acs.jmedchem.3c01613
eISSN
1520-4804
Externe Identifier
  • Clarivate Analytics Document Solution ID: DS4P5
  • PubMed Identifier: 38096359
ISSN
0022-2623
Ausgabe der Veröffentlichung
24
Zeitschrift
JOURNAL OF MEDICINAL CHEMISTRY
Paginierung
16939 - 16952
Datum der Veröffentlichung
2023
Status
Published
Titel
One-Pot Synthesis of Cereblon Proteolysis Targeting Chimeras via Photoinduced C(sp<SUP>2</SUP>)-C(sp<SUP>3</SUP>) Cross Coupling and Amide Formation for Proteolysis Targeting Chimera Library Synthesis
Sub types
  • Article
Ausgabe der Zeitschrift
66

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Autoren
  • Christine M Arndt
  • Jacqueline Bitai
  • Jessica Brunner
  • Till Opatz
  • Paola Martinelli
  • Andreas Gollner
  • Kevin R Sokol
  • Matthias Krumb
DOI
10.1021/acs.jmedchem.3c01613
eISSN
1520-4804
ISSN
0022-2623
Ausgabe der Veröffentlichung
24
Zeitschrift
Journal of Medicinal Chemistry
Sprache
en
Online publication date
2023
Paginierung
16939 - 16952
Datum der Veröffentlichung
2023
Status
Published
Herausgeber
American Chemical Society (ACS)
Herausgeber URL
http://dx.doi.org/10.1021/acs.jmedchem.3c01613
Datum der Datenerfassung
2023
Titel
One-Pot Synthesis of Cereblon Proteolysis Targeting Chimeras via Photoinduced C(sp<sup>2</sup>)–C(sp<sup>3</sup>) Cross Coupling and Amide Formation for Proteolysis Targeting Chimera Library Synthesis
Ausgabe der Zeitschrift
66

Datenquelle: Crossref

Abstract
In this study, a one-pot synthesis via photoinduced C(sp<sup>2</sup>)-C(sp<sup>3</sup>) coupling followed by amide formation to access proteolysis targeting chimeras (PROTACs) was developed. The described protocol was studied on cereblon (CRBN)-based E3-ligase binders and (+)-JQ-1, a bromodomain inhibitor, to generate BET (bromodomain and extra terminal domain) targeting protein degraders. The generated PROTACs were profiled in vitro and tested for their degradation ability with several potent candidates identified. Upfront, the individual reactions of the one-pot transformation were carefully optimized for CRBN binder functionalization and multiple heterobifunctional linker moieties were designed and synthesized. Separate scopes detailing the C(sp<sup>2</sup>)-C(sp<sup>3</sup>) coupling and one-pot PROTAC synthesis are described in this report as well as a library miniaturization study showing the high-throughput compatibility. Overall, the developed protocol provides rapid access to PROTACs in a single process, thereby allowing efficient generation of CRBN-based PROTAC libraries.
Addresses
  • Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, Vienna 1121, Austria.
Autoren
  • Christine M Arndt
  • Jacqueline Bitai
  • Jessica Brunner
  • Till Opatz
  • Paola Martinelli
  • Andreas Gollner
  • Kevin R Sokol
  • Matthias Krumb
DOI
10.1021/acs.jmedchem.3c01613
eISSN
1520-4804
Externe Identifier
  • PubMed Identifier: 38096359
Open access
false
ISSN
0022-2623
Ausgabe der Veröffentlichung
24
Zeitschrift
Journal of medicinal chemistry
Schlüsselwörter
  • Amides
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Proteolysis
  • Proteolysis Targeting Chimera
Sprache
eng
Medium
Print-Electronic
Online publication date
2023
Paginierung
16939 - 16952
Datum der Veröffentlichung
2023
Status
Published
Datum der Datenerfassung
2023
Titel
One-Pot Synthesis of Cereblon Proteolysis Targeting Chimeras via Photoinduced C(sp<sup>2</sup>)-C(sp<sup>3</sup>) Cross Coupling and Amide Formation for Proteolysis Targeting Chimera Library Synthesis.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
66

Datenquelle: Europe PubMed Central

Abstract
In this study, a one-pot synthesis via photoinduced C(sp2)-C(sp3) coupling followed by amide formation to access proteolysis targeting chimeras (PROTACs) was developed. The described protocol was studied on cereblon (CRBN)-based E3-ligase binders and (+)-JQ-1, a bromodomain inhibitor, to generate BET (bromodomain and extra terminal domain) targeting protein degraders. The generated PROTACs were profiled in vitro and tested for their degradation ability with several potent candidates identified. Upfront, the individual reactions of the one-pot transformation were carefully optimized for CRBN binder functionalization and multiple heterobifunctional linker moieties were designed and synthesized. Separate scopes detailing the C(sp2)-C(sp3) coupling and one-pot PROTAC synthesis are described in this report as well as a library miniaturization study showing the high-throughput compatibility. Overall, the developed protocol provides rapid access to PROTACs in a single process, thereby allowing efficient generation of CRBN-based PROTAC libraries.
Autoren
  • Christine M Arndt
  • Jacqueline Bitai
  • Jessica Brunner
  • Till Opatz
  • Paola Martinelli
  • Andreas Gollner
  • Kevin R Sokol
  • Matthias Krumb
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/38096359
DOI
10.1021/acs.jmedchem.3c01613
eISSN
1520-4804
Ausgabe der Veröffentlichung
24
Zeitschrift
J Med Chem
Schlüsselwörter
  • Proteolysis Targeting Chimera
  • Proteolysis
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Amides
Sprache
eng
Country
United States
Paginierung
16939 - 16952
Datum der Veröffentlichung
2023
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2023
Titel
One-Pot Synthesis of Cereblon Proteolysis Targeting Chimeras via Photoinduced C(sp2)-C(sp3) Cross Coupling and Amide Formation for Proteolysis Targeting Chimera Library Synthesis.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
66

Datenquelle: PubMed

Beziehungen:
Eigentum von

Werkzeuge