Reprogramming of Protein-Targeted Small-Molecule Medicines to RNA by Ribonuclease Recruitment.
J Am Chem Soc
; 143(33): 13044-13055, 2021 08 25.
Article
en En
| MEDLINE
| ID: mdl-34387474
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ribonucleasas
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Bencimidazoles
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Quinolonas
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MicroARNs
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Inhibidores de Proteínas Quinasas
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Bibliotecas de Moléculas Pequeñas
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Neoplasias de la Mama Triple Negativas
Límite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos