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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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.

Original languageAmerican English
Pages (from-to)13044-13055
Number of pages12
JournalJournal of the American Chemical Society
Volume143
Issue number33
DOIs
StatePublished - 25 Aug 2021
Externally publishedYes

Bibliographical note

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© 2021 American Chemical Society. All rights reserved.

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