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Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry
Bai, Nan Adeshina, Yusuf Bychov, Igor Xia, Yan Gowthaman, Ragul Gupta, Abhishek K. Johnson, David K. Lan, Lan
Bai, Nan
Adeshina, Yusuf
Bychov, Igor
Xia, Yan
Gowthaman, Ragul
Gupta, Abhishek K.
Johnson, David K.
Lan, Lan
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Pre-print
Date
2023-01-10
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Cancer and Cellular Biology
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http://dx.doi.org/10.1101/2023.01.09.523326
Abstract
RNA-binding proteins (RBPs) are key post-transcriptional regulators of gene expression, and thus underlie many important biological processes. Here, we developed a strategy that entails extracting a “hotspot pharmacophore” from the structure of a protein-RNA complex, to create a template for designing small-molecule inhibitors and for exploring the selectivity of the resulting inhibitors. We demonstrate this approach by designing inhibitors of Musashi proteins MSI1 and MSI2, key regulators of mRNA stability and translation that are upregulated in many cancers. We report this novel series of MSI1/MSI2 inhibitors is specific and active in biochemical, biophysical, and cellular assays. This study extends the paradigm of “hotspots” from protein-protein complexes to protein-RNA complexes, supports the “druggability” of RNA-binding protein surfaces, and represents one of the first rationally-designed inhibitors of non-enzymatic RNA-binding proteins. Owing to its simplicity and generality, we anticipate that this approach may also be used to develop inhibitors of many other RNA-binding proteins; we also consider the prospects of identifying potential off-target interactions by searching for other RBPs that recognize their cognate RNAs using similar interaction geometries. Beyond inhibitors, we also expect that compounds designed using this approach can serve as warheads for new PROTACs that selectively degrade RNA-binding proteins.
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Bai N, Adeshina Y, Bychov I, Xia Y, Gowthaman R, Miller SA, et al. Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry [Preprint]. bioRxiv. 2023 Jan 10. doi:10.1101/2023.01.09.523326.
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