| Literature DB >> 33689684 |
Rakesh Chatrikhi1, Callen F Feeney1, Mary J Pulvino1, Georgios Alachouzos2, Andrew J MacRae3, Zackary Falls4, Sumit Rai5, William W Brennessel2, Jermaine L Jenkins1, Matthew J Walter6, Timothy A Graubert5, Ram Samudrala4, Melissa S Jurica3, Alison J Frontier2, Clara L Kielkopf7.
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.Entities:
Keywords: S34F mutant; U2AF(35); U2AF(65); U2AF1; myelodysplastic syndrome; ribonucleoprotein targeting; spliceosome inhibition; splicing factor mutation; therapeutic strategy
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Year: 2021 PMID： 33689684 PMCID： PMC8380659 DOI： 10.1016/j.chembiol.2021.02.007
Source DB: PubMed Journal: Cell Chem Biol ISSN： 2451-9448 Impact factor: 9.039