# Small molecules that cut the RNA message of an undruggable oncogene

Source: https://onco.cc/ideas/idea-bio1-rna-targeting-small-molecules/  
OnCo record `idea-bio1-rna-targeting-small-molecules` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

If the protein cannot be drugged, target the message that makes it. Small molecules can now recognise folded shapes in RNA and recruit an enzyme that chops it up.

## Summary

Ribonuclease-targeting chimeras (RIBOTACs) and RNA-binding small molecules bind structured motifs in oncogenic transcripts and recruit RNase L. Precedent exists for microRNA precursors and for the splicing modulator class approved in spinal muscular atrophy, which proved that oral small molecules can act on RNA in humans. Candidate cancer targets include MYC regulatory elements, oncogenic lncRNAs and undruggable transcription factor messages.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: An RNA-targeted degrader reduces the target transcript by more than 70 percent in tumour tissue after oral dosing, with corresponding protein loss and tumour growth inhibition.
- Rationale: RNA structure gives sequence-specific recognition without needing a protein pocket, and risdiplam shows the pharmacology is achievable orally in patients.
- Proposed test: Select one oncogene with a well-characterised structured motif; run structure-based screening, confirm on-target transcript loss by RNA sequencing with off-target transcriptome profiling, then test in xenografts.
- Maturity: speculative
- Actor: research

## Sources

- Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017): https://doi.org/10.1038/nrc.2017.36

## Connected records

- technologies: [Oligonucleotide therapeutics](https://onco.cc/technologies/antisense-sirna/), [RNA sequencing & expression profiling](https://onco.cc/technologies/rna-seq/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/)

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