A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors
Abstract RNA methyltransferases (MTases) have recently become increasingly important in drug discovery. Yet, most frequently utilized RNA MTase assays are limited in their throughput and hamper this rapidly evolving field of medicinal chemistry. This study developed a microscale thermophoresis (MST)...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01439-9 |
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| author | Zarina Nidoieva Mark O. Sabin Tristan Dewald Annabelle C. Weldert Sabrina N. Hoba Mark Helm Fabian Barthels |
| author_facet | Zarina Nidoieva Mark O. Sabin Tristan Dewald Annabelle C. Weldert Sabrina N. Hoba Mark Helm Fabian Barthels |
| author_sort | Zarina Nidoieva |
| collection | DOAJ |
| description | Abstract RNA methyltransferases (MTases) have recently become increasingly important in drug discovery. Yet, most frequently utilized RNA MTase assays are limited in their throughput and hamper this rapidly evolving field of medicinal chemistry. This study developed a microscale thermophoresis (MST)-based split aptamer assay for enzymatic MTase investigations, improving current methodologies by offering a non-proprietary, cost-effective, and highly sensitive approach. Our findings demonstrate the assay’s effectiveness across different RNA MTases, including inhibitor characterization of METTL3/14, DNMT2, NSUN2, and S. aureus TrmD, enabling future drug discovery efforts. Using this concept, a pilot screening on the cancer drug target DNMT2 discovered several hit compounds with micromolar potency. |
| format | Article |
| id | doaj-art-b6dd457ca88a4048ab090e6f7b3b90e7 |
| institution | Kabale University |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-b6dd457ca88a4048ab090e6f7b3b90e72025-02-09T12:16:23ZengNature PortfolioCommunications Chemistry2399-36692025-02-01811910.1038/s42004-025-01439-9A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitorsZarina Nidoieva0Mark O. Sabin1Tristan Dewald2Annabelle C. Weldert3Sabrina N. Hoba4Mark Helm5Fabian Barthels6Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-UniversityInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-UniversityInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-UniversityInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-UniversityInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-UniversityInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-UniversityInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-UniversityAbstract RNA methyltransferases (MTases) have recently become increasingly important in drug discovery. Yet, most frequently utilized RNA MTase assays are limited in their throughput and hamper this rapidly evolving field of medicinal chemistry. This study developed a microscale thermophoresis (MST)-based split aptamer assay for enzymatic MTase investigations, improving current methodologies by offering a non-proprietary, cost-effective, and highly sensitive approach. Our findings demonstrate the assay’s effectiveness across different RNA MTases, including inhibitor characterization of METTL3/14, DNMT2, NSUN2, and S. aureus TrmD, enabling future drug discovery efforts. Using this concept, a pilot screening on the cancer drug target DNMT2 discovered several hit compounds with micromolar potency.https://doi.org/10.1038/s42004-025-01439-9 |
| spellingShingle | Zarina Nidoieva Mark O. Sabin Tristan Dewald Annabelle C. Weldert Sabrina N. Hoba Mark Helm Fabian Barthels A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors Communications Chemistry |
| title | A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors |
| title_full | A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors |
| title_fullStr | A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors |
| title_full_unstemmed | A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors |
| title_short | A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors |
| title_sort | microscale thermophoresis based enzymatic rna methyltransferase assay enables the discovery of dnmt2 inhibitors |
| url | https://doi.org/10.1038/s42004-025-01439-9 |
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