Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology*
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Humans
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MicroRNAs / antagonists & inhibitors*
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MicroRNAs / metabolism
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Molecular Structure
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Nephritis, Hereditary / drug therapy
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Nephritis, Hereditary / metabolism
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Quinolones / chemistry
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Quinolones / pharmacology*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / metabolism
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Ribonucleases / antagonists & inhibitors*
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Ribonucleases / metabolism
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Triple Negative Breast Neoplasms / drug therapy*
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Triple Negative Breast Neoplasms / metabolism
Substances
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4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
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Benzimidazoles
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MIRN21 microRNA, human
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MicroRNAs
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Protein Kinase Inhibitors
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Quinolones
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Small Molecule Libraries
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Receptor Protein-Tyrosine Kinases
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Ribonucleases