A synthetic small molecule stalls pre-mRNA splicing by promoting an early-stage U2AF2-RNA complex

Rakesh Chatrikhi, Callen F. Feeney, Mary J. Pulvino, Georgios Alachouzos, Andrew J. MacRae, Zackary Falls, Sumit Rai, William W. Brennessel, Jermaine L. Jenkins, Matthew J. Walter, Timothy A. Graubert, Ram Samudrala, Melissa S. Jurica, Alison J. Frontier, Clara L. Kielkopf

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Pages (from-to)1145-1157.e6
JournalCell Chemical Biology
Volume28
Issue number8
DOIs
StatePublished - Aug 19 2021

Keywords

  • S34F mutant
  • U2AF
  • U2AF
  • U2AF1
  • myelodysplastic syndrome
  • ribonucleoprotein targeting
  • spliceosome inhibition
  • splicing factor mutation
  • therapeutic strategy

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