RNA G-quadruplex (G4) structures in untranslated mRNA regions

Class

G-quadruplex-targeting small molecule (first-in-class, IV)

Pathway

Binds G4 secondary structures abundant in cancer cell mRNA UTRs, modulating gene expression post-transcriptionally to reduce tumor growth/survival

RNA G-quadruplexes (G4s) are four-stranded secondary structures that guanine-rich sequences can fold into, stabilized by stacked arrangements of four guanines held together by non-standard (Hoogsteen) hydrogen bonds, often coordinated with a central ion. These structures occur throughout the genome and transcriptome, including within the untranslated regions (UTRs) of messenger RNA that flank the protein-coding sequence. When present in UTRs, G4s can act as structural switches that influence whether and how efficiently a transcript is translated into protein, or how stable it is. Many genes associated with cell growth and survival are enriched for G4-forming sequences in their UTRs, making this structural motif an attractive point of pharmacological intervention: a small molecule that binds and stabilizes these folds can suppress translation of the associated transcripts without altering the underlying DNA sequence. Because G4s recur across multiple transcripts rather than being unique to one gene, targeting them offers a route to modulating several disease-relevant genes simultaneously through a shared structural feature. This mechanism is being explored primarily in oncology, where dysregulated expression of growth- and survival-promoting genes is a central driver of disease, and where post-transcriptional control represents a mechanistic layer distinct from conventional gene-silencing or kinase-inhibition strategies.