1. Low Molecular Weight Inhibitors Targeting the RNA-Binding Protein HuR
- Author
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Benjamin Philipp Joseph, Verena Weber, Lisa Knüpfer, Alejandro Giorgetti, Mercedes Alfonso-Prieto, Sybille Krauß, Paolo Carloni, and Giulia Rossetti
- Subjects
RNA-binding protein ,human antigen R (HuR) ,high-throughput virtual screening ,small molecule inhibitors ,RNA pulldown assay ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The RNA-binding protein human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. This protein has been progressively recognized as a relevant therapeutic target for several pathologies, like cancer, neurodegeneration, as well as inflammation. Inhibitors of mRNA binding to HuR might thus be beneficial against a variety of diseases. Here, we present the rational identification of structurally novel HuR inhibitors. In particular, by combining chemoinformatic approaches, high-throughput virtual screening, and RNA–protein pulldown assays, we demonstrate that the 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand exhibits a dose-dependent HuR inhibition effect in binding experiments. Importantly, the chemical scaffold is new with respect to the currently known HuR inhibitors, opening up a new avenue for the design of pharmaceutical agents targeting this important protein.
- Published
- 2023
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