Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer
Menée in vitro et à l'aide d'un modèle murin de cancer mammaire métastatique, cette étude met en évidence l'intérêt d'une petite molécule qui, en recrutant et activant une ribonucléase, favorise le clivage de l'ARN précurseur du microARN-21, une molécule oncogène
The human genome produces RNAs that do not code for protein but play important roles in biology, including causing disease. These RNAs are potential drug targets. Estimates suggest that there are 100-fold more potential RNA than protein drug targets. Despite this potential, small-molecule targeting of human RNA is rare as it is technically challenging. Here we describe a general and fast strategy to design small molecules from sequence to bind an RNA and subsequently cause its destruction. The approach was proven to destroy a cancer-causing RNA in a mouse model thereby inhibiting metastasis. Armed with these approaches, we can more deeply evaluate the potential of small-molecule therapeutics targeting RNAs.As the area of small molecules interacting with RNA advances, general routes to provide bioactive compounds are needed as ligands can bind RNA avidly to sites that will not affect function. Small-molecule targeted RNA degradation will thus provide a general route to affect RNA biology. A non–oligonucleotide-containing compound was designed from sequence to target the precursor to oncogenic microRNA-21 (pre–miR-21) for enzymatic destruction with selectivity that can exceed that for protein-targeted medicines. The compound specifically binds the target and contains a heterocycle that recruits and activates a ribonuclease to pre–miR-21 to substoichiometrically effect its cleavage and subsequently impede metastasis of breast cancer to lung in a mouse model. Transcriptomic and proteomic analyses demonstrate that the compound is potent and selective, specifically modulating oncogenic pathways. Thus, small molecules can be designed from sequence to have all of the functional repertoire of oligonucleotides, including inducing enzymatic degradation, and to selectively and potently modulate RNA function in vivo.