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dc.creatorBai, Nan
dc.creatorAdeshina, Yusuf
dc.creatorBychov, Igor
dc.creatorXia, Yan
dc.creatorGowthaman, Ragul
dc.creatorMiller, Sven
dc.creatorGupta, Abhishek K.
dc.creatorJohnson, David K.
dc.creatorLan, Lan
dc.creatorGolemis, Erica
dc.creatorMakhov, Petr B.
dc.creatorXu, Liang
dc.creatorPillai, Manoj M.
dc.creatorBoumber, Yanis
dc.creatorKaranicolas, John
dc.identifier.citationBai 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.
dc.description.abstractRNA-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.
dc.format.extent45 pages
dc.relation.ispartofFaculty/ Researcher Works
dc.rightsAttribution-NoDerivs CC BY-ND
dc.titleRationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry
dc.contributor.groupFox Chase Cancer Center (Temple University)
dc.description.departmentCancer and Cellular Biology
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact
dc.description.schoolcollegeLewis Katz School of Medicine
dc.temple.creatorBai, Nan
dc.temple.creatorAdeshina, Yusuf
dc.temple.creatorMiller, Sven A.
dc.temple.creatorGolemis, Erica A.
dc.temple.creatorMakhov, Petr B.
dc.temple.creatorKaranicolas, John

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