Small-molecule modulators targeting IRE1α for RNA splicing regulation and METTL16 for RNA methylation inhibition
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Date
2025
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Abstract
RNA modifications play crucial roles in regulating the biological activities of RNAs. Thus RNA-modifying proteins that carry these functions are promising targets for small-molecule modulators. Such modulators can serve as essential tool compounds for furthering understanding of RNA biology, offer new therapeutic entities for the treatment of diseases involving RNA dysregulation, and drive drug discovery and chemical biology research. The Thesis describes the identification of new chemotypes and the development of novel small-molecule inhibitors targeting two such RNA-modifying proteins, the ribonuclease IRE1α and the RNA m6A methyltransferase METTL16. Such molecules were characterized as feasible starting points for the discovery of new small-molecule drug candidates for the associated diseases. IRE1α and METTL16 are RNA-modifying proteins that play a critical role in RNA regulation, including splicing, translation, and degradation. These two proteins are involved in various human diseases, such as cancers, metabolic disorders, and neurodegenerative diseases. While targeting RNA directly with small molecules is challenging, modulating RNA function through targeting the related RNA-binding and -modifying proteins, such as IRE1α and METTL16, offers an alternative strategy. This Thesis reported a series of indole-based IRE1α inhibitors with a distinct mode of action, and a series of first-in-class aminothiazolone-based METTL16 inhibitors. These inhibitors advanced the drug discovery targeting IRE1α and METTL16, and laid the foundation for the development of RNA-targeted therapies. Further efforts in optimizing inhibitors to enhance the inhibitors' potency and selectivity, as well as designing bifunctional molecules, are expected to provide new insight into the biological functions of these molecules.
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IRE1, METTL16, Modulators
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