RT Journal Article
SR Electronic
T1 An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 584441
DO 10.1101/584441
A1 Yihui Shi
A1 Walter Bray
A1 Alexander J. Smith
A1 Wei Zhou
A1 Joy Calaoagan
A1 Chandraiah Lagisetti
A1 Lidia Sambucetti
A1 Phillip Crews
A1 R. Scott Lokey
A1 Thomas R. Webb
YR 2019
UL http://biorxiv.org/content/early/2019/03/21/584441.abstract
AB 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-030871) 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 supports 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 chemotherapeutic discovery.MOAmechanism of actionINDinvestigational new drugTESLRtriple exon skipping luciferase reporterSD6sudemycin D6HTShigh-throughput screeningASalternative splicingCLLchronic lymphocytic leukemiaMDSthe myelodysplastic syndromesPhosphorphosphorylated