AI Article Synopsis
- * A new compound discovered enhances RNA binding in a key component of the spliceosome (U2AF2) and disrupts splicing by blocking assembly at a critical stage.
- * This compound shows potential to selectively kill cells with cancer-related mutations in spliceosomal components, indicating that targeting spliceosome assembly could be an effective treatment strategy.
Article Abstract
Dysregulated pre-mRNA splicing is an emerging Achilles heel of cancers and myelodysplasias. To expand the currently limited portfolio of small-molecule drug leads, we screened for chemical modulators of the U2AF complex, which nucleates spliceosome assembly and is mutated in myelodysplasias. A hit compound specifically enhances RNA binding by a U2AF2 subunit. Remarkably, the compound inhibits splicing of representative substrates and stalls spliceosome assembly at the stage of U2AF function. Computational docking, together with structure-guided mutagenesis, indicates that the compound bridges the tandem U2AF2 RNA recognition motifs via hydrophobic and electrostatic moieties. Cells expressing a cancer-associated U2AF1 mutant are preferentially killed by treatment with the compound. Altogether, our results highlight the potential of trapping early spliceosome assembly as an effective pharmacological means to manipulate pre-mRNA splicing. By extension, we suggest that stabilizing assembly intermediates may offer a useful approach for small-molecule inhibition of macromolecular machines.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380659 | PMC |
| http://dx.doi.org/10.1016/j.chembiol.2021.02.007 | DOI Listing |
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