RNA degradation using ribonuclease targeting chimeras (RiboTACs) is a promising approach for cancer therapy. However, potential off-target degradation is a serious issue. Here, a RiboTAC is designed for tumor microenvironment triggered activation. The tumor microenvironment activated RiboTAC (TaRiboTAC) incorporates two pre-miR-21 binders, a near-infrared fluorophore IR780, an RGD targeting peptide and a phenylboronic acid caged ribonuclease recruiter. The caged ribonuclease recruiter is embedded in the molecule and exposed in acidic pH, the phenylboronic acid cage is removed by H2O2 making the TaRiboTAC responsive to the acidic and high H2O2 levels in the tumor microenvironment. It is shown the TaRiboTAC targets tumor tissue and degrades pre-miR-21. The degradation of pre-miR-21 by TaRiboTACs significantly increases the radiotherapeutic susceptibility of cancer cells achieving efficient suppression of human lung adenocarcinoma A549 tumors in living mice. Off-target effects have limite

Researchers have created a new type of drug molecule that can precisely destroy TERRA, an RNA molecule that helps certain cancer cells survive.

Researchers have created a new type of drug molecule that can precisely destroy TERRA, an RNA molecule that helps certain cancer cells survive. Using advanced "RIBOTAC" technology, their compound finds TERRA inside cells and breaks it down without harming healthy molecules. This discovery could pave the way for a new generation of RNA-based cancer treatments, targeting the disease at its genetic roots rather than just its symptoms.

Triple-negative breast cancer (TNBC) is an aggressive subtype with a high propensity for bone metastasis and limited treatment options. Although many proteins drive metastasis, most remain inaccessibl...

Key Points. The oncogene c-MYC is targetable at the mRNA level using a ribonuclease-targeting chimera (RiboTAC).MYC-RiboTAC exerts potent anti-myeloma acti

This study introduces an innovative strategy for the tumor-selective catalytic degradation of oncogenic non-coding RNA by interfacing a ribonuclease-recruiting small molecule (RIBOTAC) with an EGFR-t...

c-MYC (MYC) is an important oncogene in multiple myeloma (MM), driving MM cell proliferation, metabolism, and survival. However, MYC has been challeng…

Using ribonuclease targeting chimera (RIBOTAC) technology, fluorescent probes enable real-time visualization of RNase L localization and interaction dynamics. Here, we present a protocol to assess probe uptake, binding specificity, and RNase L co-localization in live cells using a fluorescent-based binding and competition assay combined with confocal microscopy. We provide step-by-step instructions for live-cell imaging and quantitative fluorescence analysis, enabling researchers to monitor RNA ...

Researchers have created a new type of drug molecule that can precisely destroy TERRA, an RNA molecule that helps certain cancer cells survive. Using advanced "RIBOTAC" technology, their compound find...

A research team has unveiled a small molecule that hunts down a cancer-enabling RNA and quietly erases it. Researchers have designed a groundbreaking drug molecule capable of precisely eliminating TERRA, an RNA molecule that some cancer cells rely on to survive. Using a sophisticated method known as “RIBOTAC” technology, the new compound seeks out TERRA [...]

This study introduces a selective RNA degradation strategy targeting long noncoding RNA (lncRNA) TERRA, upregulated in ALT (alternative lengthening of telomeres) cancer cells. Using ribonuclease-targ...

This study introduces a selective RNA degradation strategy targeting long noncoding RNA (lncRNA) TERRA, upregulated in ALT (alternative lengthening of telomeres) cancer cells. Using ribonuclease-targeting chimeras (RIBOTACs), RNase L is recruited to catalytically degrade TERRA, uncovering a novel approach to affect a disease associated lncRNA in ALT-driven cancers. Abstract Long noncoding RNAs (lncRNAs) regulate gene expression and play crucial roles in development and disease, including cancer. One important but still poorly understood lncRNA is TERRA (telomeric repeat-containing RNA), transcribed from telomeres and essential for telomere maintenance, genome stability, and cellular aging. TERRA adopts two structural features,R-loops and G-quadruplexes (G4s), that drive its biological activity. Its dysregulation is linked to telomere dysfunction and is prominent in Alternative Lengthening of Telomeres (ALT) cancers, where TERRA is highly upregulated and promotes telomere recombination. Here, first-in-class small molecules targeting TERRA using RIBOTAC (Ribonuclease-Targeting Chimera) technology is developed. These compounds selectively bind TERRA's G4 structures and recruit RNase L, inducing its degradation while sparing DNA G4s and other G4 RNAs. This selectivity results from ternary complex formation with RNase L and the repetitive G4 motifs enriched in TERRA. TERRA-RIBOTACs in HeLa and U2OS cells, the latter representing an ALT cancer model, are evaluated. TERRA degradation, particularly at 7p, 13q, 15q, and 20q loci, impairs telomere function and reduces colony formation. Manipulating lncRNAs like TERRA with chemical tools opens new avenues for drug development and deepens the understanding of RNA-based regulation in cancer biology.