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A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors.

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Název: A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors.
Autoři: Nidoieva, Zarina, Sabin, Mark O., Dewald, Tristan, Weldert, Annabelle C., Hoba, Sabrina N., Helm, Mark, Barthels, Fabian
Zdroj: Communications Chemistry; 2/3/2025, Vol. 8 Issue 1, p1-9, 9p
Témata: DRUG discovery, HIGH throughput screening (Drug development), RNA methylation, PHARMACEUTICAL chemistry, DRUG target
Abstrakt: 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. RNA methyltransferases (MTases) are drug targets that catalyze RNA methylation, a reaction associated to disease, but medium and high-throughput screening assays are lacking. Here, the authors develop a microscale thermophoresis-based split aptamer assay and demonstrate its sensitivity and robustness in the characterization of inhibitors against RNA MTases. [ABSTRACT FROM AUTHOR]
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Databáze: Complementary Index
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Abstrakt: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. RNA methyltransferases (MTases) are drug targets that catalyze RNA methylation, a reaction associated to disease, but medium and high-throughput screening assays are lacking. Here, the authors develop a microscale thermophoresis-based split aptamer assay and demonstrate its sensitivity and robustness in the characterization of inhibitors against RNA MTases. [ABSTRACT FROM AUTHOR]
ISSN:23993669
DOI:10.1038/s42004-025-01439-9