The beginning of a new era:pioneering direct screens for RNA modulators

In a recent study published in Nature,1 Aguilar et al.describe the small molecule X1 that targets the long non-coding RNA Xist.Upon X1 binding,Xist changes its structure,which prevents its role in X-chromosome inactivation(XCI).The vast majority of small molecule screens in drug discovery focus on targeting proteins.2,3 However,protein coding sequences merely constitute~1.5%of the human genome and only a small fraction of these proteins are currently targetable.2 In contrast,90%of the human genome is transcribed into RNA in different forms,which makes RNAs compelling targets for small molecule drugs.3 Modulating mRNAs with small molecules could be an alternative route to change the levels of the corresponding protein products and their activities,especially for currently undruggable proteins.Considering the diverse functions carried out by different classes of RNAs in cells,altering RNAs would provide a broad range of potential drug targets in the human genome.While modulating RNAs with small molecules carries a number of advantages,identifying RNA-targeting small molecules has proven difficult;previous compounds had been identified indirectly by phenotypic screens.1–3 Systematic approaches to screen for RNAtargeting compounds had been lacking.