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An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications

Yihui Shi, Walter Bray, Alexander J. Smith, Wei Zhou, Joy Calaoagan, Chandraiah Lagisetti, Lidia Sambucetti, View ORCID ProfilePhillip Crews, R. Scott Lokey, View ORCID ProfileThomas R. Webb
doi: https://doi.org/10.1101/584441
Yihui Shi
1Bioscience Division, SRI International, Menlo Park, CA 94025
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Walter Bray
2Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064
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Alexander J. Smith
2Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064
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Wei Zhou
1Bioscience Division, SRI International, Menlo Park, CA 94025
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Joy Calaoagan
1Bioscience Division, SRI International, Menlo Park, CA 94025
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Chandraiah Lagisetti
1Bioscience Division, SRI International, Menlo Park, CA 94025
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Lidia Sambucetti
1Bioscience Division, SRI International, Menlo Park, CA 94025
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Phillip Crews
2Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064
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R. Scott Lokey
2Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064
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Thomas R. Webb
1Bioscience Division, SRI International, Menlo Park, CA 94025
2Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064
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  • ORCID record for Thomas R. Webb
  • For correspondence: thomas.webb@sri.com
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ABSTRACT

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.

  • Abbreviations

    MOA
    mechanism of action
    IND
    investigational new drug
    TESLR
    triple exon skipping luciferase reporter
    SD6
    sudemycin D6
    HTS
    high-throughput screening
    AS
    alternative splicing
    CLL
    chronic lymphocytic leukemia
    MDS
    the myelodysplastic syndromes
    Phosphor
    phosphorylated
  • Copyright 
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    Posted March 21, 2019.
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    An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications
    Yihui Shi, Walter Bray, Alexander J. Smith, Wei Zhou, Joy Calaoagan, Chandraiah Lagisetti, Lidia Sambucetti, Phillip Crews, R. Scott Lokey, Thomas R. Webb
    bioRxiv 584441; doi: https://doi.org/10.1101/584441
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    An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications
    Yihui Shi, Walter Bray, Alexander J. Smith, Wei Zhou, Joy Calaoagan, Chandraiah Lagisetti, Lidia Sambucetti, Phillip Crews, R. Scott Lokey, Thomas R. Webb
    bioRxiv 584441; doi: https://doi.org/10.1101/584441

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