Kumar Deepak, Kashyap Manoj K, La Clair James J, Villa Reymundo, Spaanderman Ide, Chien Stephen, Rassenti Laura Z, Kipps Thomas J, Burkart Michael D, Castro Januario E
The Moores Cancer Center, University of California San Diego , La Jolla, California 92093, United States.
Department of Chemistry and Biochemistry, University of California , San Diego, La Jolla, California 92093-0358, United States.
ACS Chem Biol. 2016 Oct 21;11(10):2716-2723. doi: 10.1021/acschembio.6b00399. Epub 2016 Aug 8.
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.
RNA剪接失调是疾病的一个分子标志，包括各种不同且通常较为复杂的癌症。尽管RNA剪接作为治疗靶点已受到认可，但了解指导RNA剪接的复杂机制对化学生物学来说仍是一项挑战。小分子剪接调节剂的发现最近使得对异常剪接机制的评估成为可能。我们现在报告剪接调节剂选择性中的三个独特特征。首先，我们提供证据表明，剪接调节剂内的结构修饰可不同程度地改变特定基因中内含子的剪接。这些研究表明，构效关系不仅对剪接活性有影响，还包括对不同基因中特定内含子的特异性。其次，我们发现这些剪接调节剂还靶向编码剪接体自身组分的mRNA。值得注意的是，这种效应包括SF3B复合体的基因，而SF3B复合体是普拉地诺内酯B及相关剪接调节剂的作用靶点。最后，我们报告了首次观察到的与小分子剪接调节相关的时间现象。综合这三个观察结果，为未来药物化学研究以及理解剪接调节时间的关键方面提供了一个重要的新视角。
