Optimization of a Protein-Targeted Medicine into an RNA-Specific Small Molecule.
ACS Chem Biol
; 18(11): 2336-2342, 2023 11 17.
Article
en En
| MEDLINE
| ID: mdl-37870980
ABSTRACT
Protein-targeted small molecule medicines often bind RNAs and affect RNA-mediated pathways in cells. Historically, small molecule engagement and modulation of RNA have not been considered in medicine development; however, RNA should be considered both a potential on- and off-target. Kinase inhibitors have emecrged as common RNA binders with dovitinib, a classic receptor tyrosine kinase (RTK) inhibitor, inhibiting RTKs and the biogenesis of oncogenic microRNA-21 through direct engagement. In this study, we use knowledge of the molecular recognition of both protein and RNA targets by dovitinib to design molecules that specifically inhibit the RNA target but lack activity against canonical protein targets in cells. As it is now becoming apparent that RNA can be both an on- and off-target for small molecule medicines, this study lays a foundation to use design principles to maximize desired compound activity while minimizing off-target effects.
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1
Base de datos:
MEDLINE
Asunto principal:
MicroARNs
Idioma:
En
Revista:
ACS Chem Biol
Año:
2023
Tipo del documento:
Article