Design and synthesis of small molecules binders of pre-miRNA21 toward the regulation of oncogenic miRNA21

RNA has been successfully targeted by small molecules for drug discovery purposes, by taking advantage of the binding sites available following its rearrangement into secondary and tertiary structures.1 One of these validated RNA targets is pre-miR-21, a non-coding RNA linked to various cancers and other pathologies.2 This project aims to develop new selective binders to target pre-miRNA21, and, eventually, decrease the levels of miRNA21. Our starting point was an NMR fragment-based screening that identified 17 ligands.3 Interestingly, NMR recognized the nucleotides of the apical loop (AL), close to the Dicer site (A29), as potential binding site (Figure 1), opening the avenue to a structure-based design of improved pre-miRNA21 ligands.3 Two of the best binders were chosen to perform a fragment-growing campaign. We installed groups with a variety of chemical-physical features including aromaticity, the presence of multiple positive charges and of N-containing aliphatic rings to boost rigidity, π/π stacking, π/cation and ionic interactions with RNA negative backbone.