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

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 compou...

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Bibliographic Details
Published in:PloS one 2020-05, Vol.15 (5), p.e0233672-e0233672
Main Authors: Shi, Yihui, Bray, Walter, Smith, Alexander J, Zhou, Wei, Calaoagan, Joy, Lagisetti, Chandraiah, Sambucetti, Lidia, Crews, Phillip, Lokey, R Scott, Webb, Thomas R
Format: Article
Language:English
Subjects:
Antagonists
Antagonists (Biochemistry)
Antineoplastic agents
Biochemistry
Biology and Life Sciences
Cancer
Chemical compounds
Chemotherapy
Cyclin-dependent kinases
Drug discovery
Drug dosages
Drugs
Engineering and Technology
Exome sequencing
Exon skipping
Identification and classification
Kinases
Medical treatment
Medicine and Health Sciences
Methods
Modulators
mRNA
Mutation
Natural products
Pharmaceutical research
Pharmacology
Physical Sciences
Research and Analysis Methods
RNA splicing
Splicing
Therapeutic applications
Tumors
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0233672