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• W1498667661 abstract "Abstract The spliceosome has recently emerged as a new target for cancer chemotherapy and novel antitumor spliceosome targeted agents are under development. Here, we describe two types of novel pharmacodynamic assays that facilitate drug discovery and development of this intriguing class of innovative therapeutics; the first assay is useful for preclinical optimization of small‐molecule agents that target the SF 3B1 spliceosomal protein in animals, the second assay is an ex vivo validated, gel‐based assay for the measurement of drug exposure in human leukocytes. The first assay utilizes a highly specific bioluminescent splicing reporter, based on the skipping of exons 4–11 of a Luc‐ MDM 2 construct, which specifically yields active luciferase when treated with small‐molecule spliceosome modulators. We demonstrate that this reporter can be used to monitor alternative splicing in whole cells in vitro. We describe here that cell lines carrying the reporter can be used in vivo for the efficient pharmacodynamic analysis of agents during drug optimization and development. We also demonstrate dose‐ and time‐dependent on‐target activity of sudemycin D6 ( SD 6), which leads to dramatic tumor regression. The second assay relies on the treatment of freshly drawn human blood with SD 6 ex vivo treatment. Changes in alternative splicing are determined by RT ‐ PCR using genes previously identified in in vitro experiments. The Luc‐ MDM 2 alternative splicing bioluminescent reporter and the splicing changes observed in human leukocytes should allow for the more facile translation of novel splicing modulators into clinical application." @default.
• W1498667661 created "2016-06-24" @default.
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• W1498667661 date "2015-06-26" @default.
• W1498667661 modified "2023-10-16" @default.
• W1498667661 title "Pharmacodynamic assays to facilitate preclinical and clinical development of pre‐ <scp>mRNA</scp> splicing modulatory drug candidates" @default.
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• W1498667661 doi "https://doi.org/10.1002/prp2.158" @default.
• W1498667661 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4492733" @default.
• W1498667661 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26171237" @default.
• W1498667661 hasPublicationYear "2015" @default.
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