title: Molecular architecture of zinc chelating small molecules that inhibit spliceosome assembly at an early stage.
abstract: The removal of intervening sequences (introns) from a primary RNA transcript is catalyzed by the spliceosome, a large ribonucleoprotein complex. At the start of each splicing cycle, the spliceosome assembles anew in a sequentially ordered manner on the pre-mRNA intron to be removed. We describe here the identification of a series of naphthalen-2-yl hydroxamate compounds that inhibit pre-mRNA splicing in vitro with mid- to high-micromolar values of IC(50). These hydroxamates stall spliceosome assembly at the A complex stage. A structure-activity analysis of lead compounds revealed three pharmacophores that are essential for splicing inhibition. Specifically, a hydroxamate as a zinc-binding group and a 6-methoxynaphthalene cap group are both critical, and a linker chain comprising eight to nine methylene groups is also important, for the specific binding to the docking site of a target protein molecule and precise positioning of the zinc binding group. As we found no correlation between the inhibition patterns of known histone deacetylases on the one hand and pre-mRNA splicing on the other, we conclude that these compounds may function through the inhibition of the activities of other, at present, unknown spliceosome-associated zinc metalloprotein(s).
authors: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
authors: Vishal
authors: V
authors: Patil
authors: Josh C
authors: JC
authors: Canzoneri
authors: Timur R
authors: TR
authors: Samatov
authors: Reinhard
authors: R
authors: Lührmann
authors: Adegboyega K
authors: AK
authors: Oyelere
mesh_terms: D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D012322:RNA Precursors / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects; D017381:Spliceosomes / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D056572:Histone Deacetylase Inhibitors; D012322:RNA Precursors; D015032:Zinc