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

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.

• Authors: Peiyuan Zhang, Xiaohui Liu, Daniel Abegg, Toru Tanaka, Yuquan Tong, Raphael I Benhamou, Jared Baisden, Gogce Crynen, Samantha M Meyer, Michael D Cameron, Arnab K Chatterjee, Alexander Adibekian, Jessica L Childs-Disney, Matthew D Disney
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 143 Issue 33 Pg. 13044-13055 (08 25 2021) ISSN: 1520-5126 [Electronic] United States
• PMID: 34387474 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
• Benzimidazoles
• MIRN21 microRNA, human
• MicroRNAs
• Protein Kinase Inhibitors
• Quinolones
• Small Molecule Libraries
• Receptor Protein-Tyrosine Kinases
• Ribonucleases

Topics

• Benzimidazoles (chemistry, pharmacology)
• Humans
• MicroRNAs (antagonists & inhibitors, metabolism)
• Molecular Structure
• Nephritis, Hereditary (drug therapy, metabolism)
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Quinolones (chemistry, pharmacology)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Ribonucleases (antagonists & inhibitors, metabolism)
• Small Molecule Libraries (chemistry, pharmacology)
• Triple Negative Breast Neoplasms (drug therapy, metabolism)