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  Identification of small molecule inhibitors of pre-mRNA splicing.

Pawellek, A., McElroy, S., Samatov, T., Mitchell, L., Woodland, A., Ryder, U., et al. (2014). Identification of small molecule inhibitors of pre-mRNA splicing. The Journal of Biological Chemistry, 289(50), 34683-34698. doi:10.1074/jbc.M114.590976.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-6512-8 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CBDB-6
Genre: Journal Article

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 Creators:
Pawellek, A., Author
McElroy, S., Author
Samatov, T.1, Author              
Mitchell, L., Author
Woodland, A., Author
Ryder, U., Author
Gray, D., Author
Lührmann, R.1, Author              
Lamond, A., Author
Affiliations:
1Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              

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Free keywords: High Throughput Screening; RNA; RNA Splicing; Small Molecule; Spliceosome; DDD00107587; Madrasin
 Abstract: Background: There is a need for new small molecule pre-mRNA splicing inhibitors as biotools. Results: High throughput screening resulted in the identification of small molecule splicing inhibitors that are active in vitro and in cells. Conclusion: New small molecules for studying pre-mRNA splicing in vitro and in cells are identified. Significance: Small drug-like molecules are identified that modulate splicing in vitro and in cells. Eukaryotic pre-mRNA splicing is an essential step in gene expression for all genes that contain introns. In contrast to transcription and translation, few well characterized chemical inhibitors are available with which to dissect the splicing process, particularly in cells. Therefore, the identification of specific small molecules that either inhibit or modify pre-mRNA splicing would be valuable for research and potentially also for therapeutic applications. We have screened a highly curated library of 71,504 drug-like small molecules using a high throughput in vitro splicing assay. This identified 10 new compounds that both inhibit pre-mRNA splicing in vitro and modify splicing of endogenous pre-mRNA in cells. One of these splicing modulators, DDD00107587 (termed madrasin, i.e. 2-((7methoxy-4-methylquinazolin-2-yl)amino)-5,6-dimethylpyrimidin-4(3H)-one RNAsplicing inhibitor), was studied in more detail. Madrasin interferes with the early stages of spliceosome assembly and stalls spliceosome assembly at the A complex. Madrasin is cytotoxic at higher concentrations, although at lower concentrations it induces cell cycle arrest, promotes a specific reorganization of subnuclear protein localization, and modulates splicing of multiple pre-mRNAs in both HeLa and HEK293 cells.

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Language(s): eng - English
 Dates: 2014-10-032014-12-12
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1074/jbc.M114.590976
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Title: The Journal of Biological Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 289 (50) Sequence Number: - Start / End Page: 34683 - 34698 Identifier: -