Reprogramming of Protein-Targeted Small-Molecule Medicines to RNA by Ribonuclease Recruitment

Reprogramming
known medicines for a novel target with activity
and selectivity over the canonical target is challenging. By studying
the binding interactions between RNA folds and known small-molecule
medicines and mining the resultant dataset across human RNAs, we identified
that Dovitinib, a receptor tyrosine kinase (RTK) inhibitor, binds
the precursor to microRNA-21 (pre-miR-21). Dovitinib was rationally
reprogrammed for pre-miR-21 by using it as an RNA recognition element
in a chimeric compound that also recruits RNase L to induce the RNA’s
catalytic degradation. By enhancing the inherent RNA-targeting activity
and decreasing potency against canonical RTK protein targets in cells,
the chimera shifted selectivity for pre-miR-21 by 2500-fold, alleviating
disease progression in mouse models of triple-negative breast cancer
and Alport Syndrome, both caused by miR-21 overexpression. Thus, targeted
degradation can dramatically improve selectivity even across different
biomolecules, i.e., protein versus RNA.