Covalent S-Adenosylhomocysteine-Based DNA Methyltransferase 2 Inhibitors with a New Type of Aryl Warhead
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Marvin Schwickert
- Robert A Zimmermann
- Tanja Habeck
- Sabrina N Hoba
- Zarina Nidoieva
- Tim R Fischer
- Martin M Stark
- Christian Kersten
- Frederik Lermyte
- Mark Helm
- Tanja Schirmeister
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000985552000001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1021/acsmedchemlett.3c00062
- Externe Identifier
- Clarivate Analytics Document Solution ID: I5WF3
- PubMed Identifier: 37312859
- ISSN
- 1948-5875
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- ACS MEDICINAL CHEMISTRY LETTERS
- Schlüsselwörter
- DNMT2
- covalent SAH-based inhibitors
- aryl warhead
- Topliss scheme
- microscale thermophoresis
- protein mass spectrometry
- Paginierung
- 777 - 787
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Titel
- Covalent S-Adenosylhomocysteine-Based DNA Methyltransferase 2 Inhibitors with a New Type of Aryl Warhead
- Sub types
- Article
- Ausgabe der Zeitschrift
- 14
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Autoren
- Marvin Schwickert
- Robert A Zimmermann
- Tanja Habeck
- Sabrina N Hoba
- Zarina Nidoieva
- Tim R Fischer
- Martin M Stark
- Christian Kersten
- Frederik Lermyte
- Mark Helm
- Tanja Schirmeister
- DOI
- 10.1021/acsmedchemlett.3c00062
- eISSN
- 1948-5875
- ISSN
- 1948-5875
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- ACS Medicinal Chemistry Letters
- Sprache
- en
- Online publication date
- 2023
- Paginierung
- 777 - 787
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Herausgeber
- American Chemical Society (ACS)
- Herausgeber URL
- http://dx.doi.org/10.1021/acsmedchemlett.3c00062
- Datum der Datenerfassung
- 2023
- Titel
- Covalent <i>S</i>-Adenosylhomocysteine-Based DNA Methyltransferase 2 Inhibitors with a New Type of Aryl Warhead
- Ausgabe der Zeitschrift
- 14
Datenquelle: Crossref
- Abstract
- The DNA methyltransferase 2 (DNMT2) is an RNA modifying enzyme associated with pathophysiological processes, such as mental and metabolic disorders or cancer. Although the development of methyltransferase inhibitors remains challenging, DNMT2 is not only a promising target for drug discovery, but also for the development of activity-based probes. Here, we present covalent SAH-based DNMT2 inhibitors decorated with a new type of aryl warhead. Based on a noncovalent DNMT2 inhibitor with <i>N</i>-benzyl substituent, the <i>Topliss</i> scheme was followed for optimization. The results showed that electron-deficient benzyl moieties highly increased affinity. By decorating the structures with strong electron-withdrawing moieties and leaving groups, we adjusted the electrophilicity to create covalent DNMT2 inhibitors. A 4-bromo-3-nitrophenylsulfonamide-decorated SAH derivative (<b>80</b>) turned out to be the most potent (IC<sub>50</sub> = 1.2 ± 0.1 μM) and selective inhibitor. Protein mass spectrometry confirmed the covalent reaction with the catalytically active cysteine-79.
- Addresses
- Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
- Autoren
- Marvin Schwickert
- Robert A Zimmermann
- Tanja Habeck
- Sabrina N Hoba
- Zarina Nidoieva
- Tim R Fischer
- Martin M Stark
- Christian Kersten
- Frederik Lermyte
- Mark Helm
- Tanja Schirmeister
- DOI
- 10.1021/acsmedchemlett.3c00062
- eISSN
- 1948-5875
- Externe Identifier
- PubMed Identifier: 37312859
- Funding acknowledgements
- Deutsche Forschungsgemeinschaft: 461372424
- Fonds der Chemischen Industrie:
- Deutsche Forschungsgemeinschaft: 439669440 TRR319 RMaP TP A01
- Deutsche Forschungsgemeinschaft: C01
- Hessisches Ministerium f?r Wissenschaft und Kunst:
- Volkswagen Foundation:
- Deutsche Forschungsgemeinschaft: C03
- Open access
- false
- ISSN
- 1948-5875
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- ACS medicinal chemistry letters
- Sprache
- eng
- Medium
- Electronic-eCollection
- Online publication date
- 2023
- Paginierung
- 777 - 787
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Datum der Datenerfassung
- 2023
- Titel
- Covalent <i>S</i>-Adenosylhomocysteine-Based DNA Methyltransferase 2 Inhibitors with a New Type of Aryl Warhead.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 14
Datenquelle: Europe PubMed Central
- Abstract
- The DNA methyltransferase 2 (DNMT2) is an RNA modifying enzyme associated with pathophysiological processes, such as mental and metabolic disorders or cancer. Although the development of methyltransferase inhibitors remains challenging, DNMT2 is not only a promising target for drug discovery, but also for the development of activity-based probes. Here, we present covalent SAH-based DNMT2 inhibitors decorated with a new type of aryl warhead. Based on a noncovalent DNMT2 inhibitor with N-benzyl substituent, the Topliss scheme was followed for optimization. The results showed that electron-deficient benzyl moieties highly increased affinity. By decorating the structures with strong electron-withdrawing moieties and leaving groups, we adjusted the electrophilicity to create covalent DNMT2 inhibitors. A 4-bromo-3-nitrophenylsulfonamide-decorated SAH derivative (80) turned out to be the most potent (IC50 = 1.2 ± 0.1 μM) and selective inhibitor. Protein mass spectrometry confirmed the covalent reaction with the catalytically active cysteine-79.
- Date of acceptance
- 2023
- Autoren
- Marvin Schwickert
- Robert A Zimmermann
- Tanja Habeck
- Sabrina N Hoba
- Zarina Nidoieva
- Tim R Fischer
- Martin M Stark
- Christian Kersten
- Frederik Lermyte
- Mark Helm
- Tanja Schirmeister
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/37312859
- DOI
- 10.1021/acsmedchemlett.3c00062
- Externe Identifier
- PubMed Central ID: PMC10258905
- ISSN
- 1948-5875
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- ACS Med Chem Lett
- Sprache
- eng
- Country
- United States
- Paginierung
- 777 - 787
- Datum der Veröffentlichung
- 2023
- Status
- Published online
- Titel
- Covalent S-Adenosylhomocysteine-Based DNA Methyltransferase 2 Inhibitors with a New Type of Aryl Warhead.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 14
Datenquelle: PubMed
- Beziehungen:
- Eigentum von