Projects per year
Abstract
Eukaryotic pre-mRNA splicing is an essential step in gene expression for all genes that contain introns. In contrast with 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 RNA splicing 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, while 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.
Original language | English |
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Pages (from-to) | 34683-34698 |
Number of pages | 16 |
Journal | Journal of Biological Chemistry |
Volume | 289 |
Issue number | 50 |
Early online date | 3 Oct 2014 |
DOIs | |
Publication status | Published - 12 Dec 2014 |
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Dive into the research topics of 'Identification of small molecule inhibitors of pre-mRNA splicing'. Together they form a unique fingerprint.Projects
- 1 Finished
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Strategic Award: Wellcome Trust Technology Platform
Blow, J. (Investigator), Lamond, A. (Investigator) & Owen-Hughes, T. (Investigator)
1/01/13 → 30/09/18
Project: Research
Research output
- 58 Citations
- 1 Comment/debate
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Identification of small molecule inhibitors of pre-mRNA splicing
Pawallek, A., McElroy, S., Samatov, T., Mitchell, L., Woodland, A., Ryder, U., Gray, D., Lührmann, R. & Lamond, A. I., 6 Mar 2015, In: Journal of Biological Chemistry. 290, 10, 1 p.Research output: Contribution to journal › Comment/debate › peer-review
Open Access5 Citations (Scopus)