An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications
An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications
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.
Shi Yihui、Smith Alexander J.、Zhou Wei、Calaoagan Joy、Lagisetti Chandraiah、Lokey R. Scott、Crews Phillip、Sambucetti Lidia、Bray Walter、Webb Thomas R.
Bioscience Division, SRI InternationalDepartment of Chemistry and Biochemistry, University of CaliforniaBioscience Division, SRI InternationalBioscience Division, SRI InternationalBioscience Division, SRI InternationalDepartment of Chemistry and Biochemistry, University of CaliforniaDepartment of Chemistry and Biochemistry, University of CaliforniaBioscience Division, SRI InternationalDepartment of Chemistry and Biochemistry, University of CaliforniaBioscience Division, SRI International||Department of Chemistry and Biochemistry, University of California
医学研究方法肿瘤学药学
SpliceosomeRNA processinghigh-throughput screeningmodulators of pre-mRNA splicingkinase inhibitorscancer
Shi Yihui,Smith Alexander J.,Zhou Wei,Calaoagan Joy,Lagisetti Chandraiah,Lokey R. Scott,Crews Phillip,Sambucetti Lidia,Bray Walter,Webb Thomas R..An Exon Skipping Screen Identifies Antitumor Drugs That Are Potent Modulators of Pre-mRNA Splicing, Suggesting New Therapeutic Applications[EB/OL].(2025-03-28)[2025-05-03].https://www.biorxiv.org/content/10.1101/584441.点此复制
评论