title: Selectivity in Small Molecule Splicing Modulation.
abstract: The dysregulation of RNA splicing is a molecular hallmark of disease, including different and often complex cancers. While gaining recognition as a target for therapeutic discovery, understanding the complex mechanisms guiding RNA splicing remains a challenge for chemical biology. The discovery of small molecule splicing modulators has recently enabled an evaluation of the mechanisms of aberrant splicing. We now report on three unique features within the selectivity of splicing modulators. First, we provide evidence that structural modifications within a splicing modulator can alter the splicing of introns in specific genes differently. These studies indicate that structure activity relationships not only have an effect on splicing activity but also include specificity for specific introns within different genes. Second, we find that these splicing modulators also target the mRNAs encoding components of the spliceosome itself. Remarkably, this effect includes the genes for the SF3B complex, a target of pladienolide B and related splicing modulators. Finally, we report on the first observation of a temporal phenomenon associated with small molecule splicing modulation. Combined, these three observations provide an important new perspective for the exploration of splicing modulation in terms of both future medicinal chemistry programs as well as understanding the key facets underlying its timing.
authors: The Moores Cancer Center, University of California San Diego , La Jolla, California 92093, United States.
authors: Deepak
authors: D
authors: Kumar
authors: The Moores Cancer Center, University of California San Diego , La Jolla, California 92093, United States.
authors: Manoj K
authors: MK
authors: Kashyap
authors: Department of Chemistry and Biochemistry, University of California , San Diego, La Jolla, California 92093-0358, United States.
authors: James J
authors: JJ
authors: La Clair
authors: Department of Chemistry and Biochemistry, University of California , San Diego, La Jolla, California 92093-0358, United States.
authors: Reymundo
authors: R
authors: Villa
authors: The Moores Cancer Center, University of California San Diego , La Jolla, California 92093, United States.
authors: Ide
authors: I
authors: Spaanderman
authors: The Moores Cancer Center, University of California San Diego , La Jolla, California 92093, United States.
authors: Stephen
authors: S
authors: Chien
authors: The Moores Cancer Center, University of California San Diego , La Jolla, California 92093, United States.|CLL Research Consortium, and Department of Medicine, University of California , San Diego, La Jolla, California 92093-0358, United States.
authors: Laura Z
authors: LZ
authors: Rassenti
authors: The Moores Cancer Center, University of California San Diego , La Jolla, California 92093, United States.|CLL Research Consortium, and Department of Medicine, University of California , San Diego, La Jolla, California 92093-0358, United States.
authors: Thomas J
authors: TJ
authors: Kipps
authors: Department of Chemistry and Biochemistry, University of California , San Diego, La Jolla, California 92093-0358, United States.
authors: Michael D
authors: MD
authors: Burkart
authors: The Moores Cancer Center, University of California San Diego , La Jolla, California 92093, United States.|CLL Research Consortium, and Department of Medicine, University of California , San Diego, La Jolla, California 92093-0358, United States.
authors: Januario E
authors: JE
authors: Castro
mesh_terms: D017398:Alternative Splicing; D007438:Introns; D054852:Small Molecule Libraries
chemical_list: D054852:Small Molecule Libraries