RNA-binding proteins (RBPs) regulate the life cycle of target mRNAs by controlling splicing, polyadenylation, stability, localization and translation, and they also modulate function of non-coding RNAs. Because of their crucial roles in many diverse cellular processes, RBPs are key targets for therapeutic intervention in a variety of human diseases ranging from cancers to neurodegeneration. We have recently developed a new and unique computational approach for designing inhibitors of a given RBP, starting from its structure in complex with RNA. We have validated this approach by applying it to three separate RBPs, and in each case we have identified inhibitors of our target proteins. Nonetheless, there is room for further improvement in the compounds we identify using this method. Here, we propose to extend this computational approach, to improve the initial hit compounds? potency, selectivity, and diversity. With these enhancements in place, this approach will provide new chemical tools to explore the biology of individual RBPs at unprecedented detail. To facilitate rapid and broad adoption of this method, we will also make the computational tools accessible through a webserver, so that the community of researchers wishing to design inhibitors for their own RBPs of interest will be able to easily use them. This research is expected to have an important positive impact because it will provide new insights and tools to address the distinct challenges associated with finding small-molecule inhibitors of protein-RNA interactions. This contribution is significant because a broad assortment of human diseases stem from disregulation of protein-RNA interactions, positioning such inhibitors as potential starting points for developing a variety of new therapeutic agents.
This research is expected to have an important positive impact because it will provide new insights and tools to address the distinct challenges associated with finding small-molecule inhibitors of protein-RNA interactions. This contribution is significant because a broad assortment of human diseases stem from disregulation of protein-RNA interactions, positioning such inhibitors as potential starting points for developing a variety of new therapeutic agents.
| Zhang, Hanghang; Pandey, Somnath; Travers, Meghan et al. (2018) Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer. Cell 175:1244-1258.e26 |
