ideasIdea
Small molecules that cut the RNA message of an undruggable oncogene
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.
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.
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.
What would test it
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
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
8
Bottlenecks it attacks
- The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.