Discovery of Inhibitors of DNA Methyltransferase 2, an Epitranscriptomic Modulator and Potential Target for Cancer Treatment
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Marvin Schwickert
- Tim R Fischer
- Robert A Zimmermann
- Sabrina N Hoba
- J Laurenz Meidner
- Marlies Weber
- Moritz Weber
- Martin M Stark
- Jonas Koch
- Nathalie Jung
- Christian Kersten
- Maike Windbergs
- Frank Lyko
- Mark Helm
- Tanja Schirmeister
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000830819400001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1021/acs.jmedchem.2c00388
- eISSN
- 1520-4804
- Externe Identifier
- Clarivate Analytics Document Solution ID: 3L9IB
- PubMed Identifier: 35849534
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 14
- Zeitschrift
- JOURNAL OF MEDICINAL CHEMISTRY
- Paginierung
- 9750 - 9788
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Titel
- Discovery of Inhibitors of DNA Methyltransferase 2, an Epitranscriptomic Modulator and Potential Target for Cancer Treatment
- Sub types
- Article
- Ausgabe der Zeitschrift
- 65
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Autoren
- Marvin Schwickert
- Tim R Fischer
- Robert A Zimmermann
- Sabrina N Hoba
- J Laurenz Meidner
- Marlies Weber
- Moritz Weber
- Martin M Stark
- Jonas Koch
- Nathalie Jung
- Christian Kersten
- Maike Windbergs
- Frank Lyko
- Mark Helm
- Tanja Schirmeister
- DOI
- 10.1021/acs.jmedchem.2c00388
- eISSN
- 1520-4804
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 14
- Zeitschrift
- Journal of Medicinal Chemistry
- Sprache
- en
- Online publication date
- 2022
- Paginierung
- 9750 - 9788
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Herausgeber
- American Chemical Society (ACS)
- Herausgeber URL
- http://dx.doi.org/10.1021/acs.jmedchem.2c00388
- Datum der Datenerfassung
- 2023
- Titel
- Discovery of Inhibitors of DNA Methyltransferase 2, an Epitranscriptomic Modulator and Potential Target for Cancer Treatment
- Ausgabe der Zeitschrift
- 65
Datenquelle: Crossref
- Abstract
- Selective manipulation of the epitranscriptome could be beneficial for the treatment of cancer and also broaden the understanding of epigenetic inheritance. Inhibitors of the tRNA methyltransferase DNMT2, the enzyme catalyzing the <i>S</i>-adenosylmethionine-dependent methylation of cytidine 38 to 5-methylcytidine, were designed, synthesized, and analyzed for their enzyme-binding and -inhibiting properties. For rapid screening of potential DNMT2 binders, a microscale thermophoresis assay was established. Besides the natural inhibitors <i>S</i>-adenosyl-l-homocysteine (SAH) and sinefungin (SFG), we identified new synthetic inhibitors based on the structure of <i>N</i>-adenosyl-2,4-diaminobutyric acid (Dab). Structure-activity relationship studies revealed the amino acid side chain and a Y-shaped substitution pattern at the 4-position of Dab as crucial for DNMT2 inhibition. The most potent inhibitors are alkyne-substituted derivatives, exhibiting similar binding and inhibitory potencies as the natural compounds SAH and SFG. CaCo-2 assays revealed that poor membrane permeabilities of the acids and rapid hydrolysis of an ethylester prodrug might be the reasons for the insufficient activity in cellulo.
- Addresses
- Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
- Autoren
- Marvin Schwickert
- Tim R Fischer
- Robert A Zimmermann
- Sabrina N Hoba
- J Laurenz Meidner
- Marlies Weber
- Moritz Weber
- Martin M Stark
- Jonas Koch
- Nathalie Jung
- Christian Kersten
- Maike Windbergs
- Frank Lyko
- Mark Helm
- Tanja Schirmeister
- DOI
- 10.1021/acs.jmedchem.2c00388
- eISSN
- 1520-4804
- Externe Identifier
- PubMed Identifier: 35849534
- Funding acknowledgements
- Deutsche Forschungsgemeinschaft:
- Open access
- false
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 14
- Zeitschrift
- Journal of medicinal chemistry
- Schlüsselwörter
- Caco-2 Cells
- Humans
- Neoplasms
- Methyltransferases
- S-Adenosylhomocysteine
- S-Adenosylmethionine
- Archaeal Proteins
- DNA
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2022
- Paginierung
- 9750 - 9788
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Datum der Datenerfassung
- 2022
- Titel
- Discovery of Inhibitors of DNA Methyltransferase 2, an Epitranscriptomic Modulator and Potential Target for Cancer Treatment.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 65
Datenquelle: Europe PubMed Central
- Abstract
- Selective manipulation of the epitranscriptome could be beneficial for the treatment of cancer and also broaden the understanding of epigenetic inheritance. Inhibitors of the tRNA methyltransferase DNMT2, the enzyme catalyzing the S-adenosylmethionine-dependent methylation of cytidine 38 to 5-methylcytidine, were designed, synthesized, and analyzed for their enzyme-binding and -inhibiting properties. For rapid screening of potential DNMT2 binders, a microscale thermophoresis assay was established. Besides the natural inhibitors S-adenosyl-l-homocysteine (SAH) and sinefungin (SFG), we identified new synthetic inhibitors based on the structure of N-adenosyl-2,4-diaminobutyric acid (Dab). Structure-activity relationship studies revealed the amino acid side chain and a Y-shaped substitution pattern at the 4-position of Dab as crucial for DNMT2 inhibition. The most potent inhibitors are alkyne-substituted derivatives, exhibiting similar binding and inhibitory potencies as the natural compounds SAH and SFG. CaCo-2 assays revealed that poor membrane permeabilities of the acids and rapid hydrolysis of an ethylester prodrug might be the reasons for the insufficient activity in cellulo.
- Autoren
- Marvin Schwickert
- Tim R Fischer
- Robert A Zimmermann
- Sabrina N Hoba
- J Laurenz Meidner
- Marlies Weber
- Moritz Weber
- Martin M Stark
- Jonas Koch
- Nathalie Jung
- Christian Kersten
- Maike Windbergs
- Frank Lyko
- Mark Helm
- Tanja Schirmeister
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/35849534
- DOI
- 10.1021/acs.jmedchem.2c00388
- eISSN
- 1520-4804
- Ausgabe der Veröffentlichung
- 14
- Zeitschrift
- J Med Chem
- Schlüsselwörter
- Archaeal Proteins
- Caco-2 Cells
- DNA
- Humans
- Methyltransferases
- Neoplasms
- S-Adenosylhomocysteine
- S-Adenosylmethionine
- Sprache
- eng
- Country
- United States
- Paginierung
- 9750 - 9788
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2022
- Titel
- Discovery of Inhibitors of DNA Methyltransferase 2, an Epitranscriptomic Modulator and Potential Target for Cancer Treatment.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 65
Datenquelle: PubMed
- Beziehungen:
- Eigentum von