Smart drug becomes a guided missile for cancer RNA

HQ Team 

15 November, 2025: Scientists at the Hebrew University of Jerusalem have unveiled the first drug-like molecule purpose-built to seek out and shred a previously obscure RNA structure that many solid tumours need to stay alive. The molecule, described  in Advanced Science, reduced levels of the telomeric repeat-containing RNA (TERRA) in cancer cells within hours and halted their proliferation at doses 100-fold lower than those that bothered healthy cells.  

TERRA is a long non-coding RNA transcribed from chromosome ends. It helps maintain the ends of chromosomes — the regions of DNA that support cell stability and overall health. Although discovered 15 years ago, its druggability was deemed near-impossible because it folds into G-quadruplexes—tight, four-stranded knots—only transiently and shares sequence motifs with essential RNAs. The Israeli team exploited two quirks of cancer biology: aggressive tumours over-produce TERRA, and the G-quadruplex form is enriched in the Alternative Lengthening of Telomeres (ALT) pathway used by up to 15 % of sarcomas, gliomas and paediatric brain cancers . 

Designing a molecular assassin

Led by chemical biologist Dr Raphael I. Benhamou, the researchers converted a known G-quadruplex-binding ligand into a RIBOTAC (Ribonuclease-Targeting Chimera). One end of the chimera clamps onto the RNA quadruplex; the other end flag-waves for RNase L, a native antiviral enzyme that dices RNA. Because RNase L is catalytic, a single drug molecule can orchestrate multiple cleavage events, explaining why nanomolar concentrations collapse TERRA while leaving housekeeping RNAs intact . 

“We’ve created a tool that acts like a guided missile for bad RNA,” said Dr. Benhamou. “It can find TERRA inside cancer cells and make it disappear — without harming healthy parts of the cell. We basically reprogrammed a shape-recognition event into an execution order. The cell’s own shredder does the disposal.”

In experiments using cancer cell lines such as HeLa and U2OS cells (which represent a hard-to-treat type of cancer), the treatment lowered TERRA levels and slowed cancer cell growth. 

Beyond ALT cancers

Although the study focused on ALT-driven tumours, TERRA also restrains telomerase in about 85 % of human cancers. Benhamou therefore predicts modest TERRA depletion might sensitise telomerase-positive tumours to conventional telomerase inhibitors, whereas deeper suppression could cripple normal stem-cell compartments. “Dosing and delivery will decide the clinical index,” he concedes .

Most approved anticancer drugs target proteins, yet only 0.05 % of the human genome codes for druggable enzymes. By contrast, 70 % is transcribed into RNA, much of it dysregulated in disease. Commentators see the work as a milestone in the ascent of RNA as the third pharmacological pillar, alongside small molecules and biologics. 

“This is the first demonstration that you can take a non-coding RNA with a complex secondary structure and delete it pharmacologically,” said Dr Matthew Disney, Scripps Research, who pioneered RIBOTACs but was not involved in the study. “It validates the platform for any disease driven by a structured RNA.” 

Next steps

The Hebrew University group, together with the technology-transfer company Yissum, is scaling up GMP synthesis and plans mouse xenograft efficacy studies before the end of 2025. They are also screening additional G-quadruplex RNAs—such as those in the MYC and BCL-2 oncogenes—for similar vulnerability.

If toxicology holds, a first-in-human trial could open within three years, initially in ALT-positive sarcoma patients who have exhausted standard care. 

For a subset of cancers with no targeted options, a small molecule that quietly erases their immortality RNA may finally level the playing field.