1. Academic Validation
  2. Identification of small molecule inhibitors of pre-mRNA splicing

Identification of small molecule inhibitors of pre-mRNA splicing

  • J Biol Chem. 2014 Dec 12;289(50):34683-98. doi: 10.1074/jbc.M114.590976.
Andrea Pawellek 1 Stuart McElroy 2 Timur Samatov 3 Lee Mitchell 2 Andrew Woodland 2 Ursula Ryder 1 David Gray 2 Reinhard Lührmann 3 Angus I Lamond 4
Affiliations

Affiliations

  • 1 From the Centre of Gene Regulation and Expression and.
  • 2 the Drug Discovery Unit, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom and.
  • 3 the Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
  • 4 From the Centre of Gene Regulation and Expression and a.i.lamond@dundee.ac.uk.
Abstract

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.

Keywords

DDD00107587; High Throughput Screening; Madrasin; RNA; RNA Splicing; Small Molecule; Spliceosome.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100236
    99.90%, Splicing 抑制剂