An exon skipping screen identifies antitumor drugs that are potent modulators of pre-mRNA splicing, suggesting new therapeutic applications

PLoS One. 2020 May 29;15(5):e0233672. doi: 10.1371/journal.pone.0233672. eCollection 2020.


Agents that modulate pre-mRNA splicing are of interest in multiple therapeutic areas, including cancer. We report our recent screening results with the application of a cell-based Triple Exon Skipping Luciferase Reporter (TESLR) using a library that is composed of FDA approved drugs, clinical compounds, and mechanistically characterized tool compounds. Confirmatory assays showed that three clinical antitumor therapeutic candidates (milciclib, PF-3758309 and PF-562271) are potent splicing modulators and that these drugs are, in fact, nanomolar inhibitors of multiple kinases involved in the regulation the spliceosome. We also report the identification of new SF3B1 antagonists (sudemycinol C and E) and show that these antagonists can be used to develop a displacement assay for SF3B1 small molecule ligands. These results further support the broad potential for the development of agents that target the spliceosome for the treatment of cancer and other diseases, as well as new avenues for the discovery of new chemotherapeutic agents for a range of diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor / methods*
  • Exons / drug effects*
  • Humans
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Protein Kinase Inhibitors / pharmacology
  • RNA Precursors / genetics*
  • RNA Splicing / drug effects*


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • RNA Precursors

Grant support

This work was supported by the National Institute of Health (NIH Cancer Institute (NCI CA2147590 (to T.R.W.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.