Abstract

The growing awareness of the role of RNA in human disease has motivated significant efforts to discover drug-like small molecules that target RNA. However, high throughput screening campaigns report very low hit rates and generally identify compounds with weak affinity, while most structures reported in Academic studies also lack the pharmacological properties of successful drugs. Even FDA-approved RNA-targeting drugs have only weak (10 M) binding activity. Thus, it is often stated that only complex RNA structures, such as the ribosome or riboswitches, are amenable to small molecule chemistry. We report that the kinase inhibitor Palbociclib/Ibrance is a nM ligand for the HIV-1 TAR. It inhibits recruitment of the positive transcription elongation factor complex at nM concentrations and discriminates >20 fold. We further show that RNA binding can be fully decoupled from kinase inhibition, yielding a new molecule with even higher affinity for RNA. We thus demonstrate that nM affinity, specificity, and potent biochemical activity against undruggable RNAs can be found in the chemical space of blockbuster drugs.