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Nanomole-Scale Libraries For Medicinal Chemistry Of RNAMethyltransferases

ORCID
0009-0001-4511-7507
Affiliation
Institute of Pharmaceutical and Medicinal Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D 55128 Mainz, Germany
Frey, Ariane Felicitas;
Affiliation
Institute of Pharmaceutical and Medicinal Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D 55128 Mainz, Germany
Kadenbach, Valerie;
Affiliation
Institute of Pharmaceutical and Medicinal Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D 55128 Mainz, Germany
Weldert, Annabelle C.;
Affiliation
Institute of Pharmaceutical and Medicinal Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D 55128 Mainz, Germany
Meidner, Laurenz;
Affiliation
Institute of Pharmaceutical and Medicinal Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D 55128 Mainz, Germany
Zimmermann, Robert;
Affiliation
Institute of Pharmaceutical and Medicinal Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D 55128 Mainz, Germany
Sabin, Mark;
Affiliation
Institute of Pharmaceutical and Medicinal Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D 55128 Mainz, Germany
Nidoieva, Zarina;
Affiliation
Institute of Pharmaceutical and Medicinal Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D 55128 Mainz, Germany
Hoba, Sabrina N.;
Affiliation
Institute of Pharmaceutical and Medicinal Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D 55128 Mainz, Germany
Schirmeister, Tanja;
Affiliation
Institute of Pharmaceutical and Medicinal Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, D 55128 Mainz, Germany
Barthels, Fabian

The speed of drug development is increasing, driven by the need for new inhibitors and modulators of medicinal-relevant enzymes. Nanomole-scale chemistry coupled with high-throughput screening enables the fast discovery of unexpected ligand chemotypes and the development of novel inhibitors that may not be anticipated through rational drug design strategies.

This strategy could be employed for drug discovery on RNA-modifying enzymes. Dysregulation of RNA modifications has been linked to various disease phenotypes while RNA-modifying enzyme inhibitors have recently emerged as a cutting-edge topic in drug discovery, including the first-in-class clinically investigated drug STC-15 targeting METTL3/14. Our focus includes the development of fluorescent probes for high-throughput microscale thermophoresis (MST) and Fluorescence Polarization (FP)-displacement assays and the identification of new selective inhibitors for RNA-methyltransferases.

Yet, a few drug development campaigns have focused on the 5-methylcytosine (m5C)-modification, introduced by the DNA methyltransferase 2 (DNMT2). A high-throughput screening with DNA-encoded library libraries (DEL) resulted in the identification of novel selective allosteric-site binders and inhibitors with a low-micromolar affinity for the DNMT2 enzyme. The crystallographic structure shows that the DEL ligand occupies a cryptic allosteric pocket and inhibition is explained by the reorganization of an active site loop, and thus indirectly influences the function of DNMT2.

Furthermore, a combinatorial alkyne/azide nanoSAR approach could be harnessed for the development of selective fluorescent probes for in vitro characterization of methyltransferase ligand binding. The MST-and FP-assays enable the opportunity for fast and easy discrimination between non-binders and binders and the determination of ligand binding affinities. This approach could be used for a high-throughput drug screening campaign which led to the identification of the first-in-class inhibitor for METTL1, anm7G RNA-methyltransferase that is found to play a crucial role in the oncogenesis of various types of cancer.

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