CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours
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Updated: Mar 7, 2026
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
Hong Xu1, Marco Di Antonio2,3, Steven McKinney1
1Department of Molecular Oncology, British Columbia Cancer Research Centre, and Department of Pathology and Laboratory Medicine, University of British Columbia, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
Abstract:
G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016).
Insights
CX-5461 stabilizes G-quadruplex DNA, showing promise for treating BRCA-deficient cancers. This drug induces DNA damage, proving lethal to cancer cells lacking repair mechanisms like homologous recombination (HR) and non-homologous end joining (NHEJ).
Area of Science:
- Molecular Biology
- Cancer Therapeutics
- Genetics
Background:
- G-quadruplex (G4) DNA structures are implicated in crucial cellular functions.
- Targeting G4 DNA presents a promising strategy for cancer therapy.
- BRCA deficiencies confer sensitivity to certain DNA-damaging agents.
Purpose of the Study:
- To investigate CX-5461 as a G-quadruplex stabilizer and evaluate its efficacy in cancer models.
- To determine the mechanism of action and identify cancer types susceptible to CX-5461.
- To assess the role of DNA repair pathways in response to CX-5461 treatment.
Main Methods:
- In vitro G-quadruplex stabilization assays.
- In vitro and in vivo cancer models, including BRCA-deficient cell lines and patient-derived xenografts.
- Analysis of DNA damage induction (replication fork blockage, ssDNA gaps/breaks) and repair pathway involvement (BRCA, NHEJ).
Main Results:
- CX-5461 functions as a G-quadruplex stabilizer with specific toxicity towards BRCA-deficient cancers.
- The drug induces replication fork stalling and DNA breaks, requiring BRCA and NHEJ for repair.
- Tumors resistant to PARP inhibition also showed sensitivity to CX-5461.
- Failure of DNA repair pathways leads to cancer cell lethality.
Conclusions:
- G-quadruplex targeting, exemplified by CX-5461, is a viable therapeutic strategy for cancers with deficiencies in homologous recombination (HR) and non-homologous end joining (NHEJ) DNA repair.
- CX-5461 demonstrates potential for treating BRCA-deficient tumors and those resistant to other therapies.
- CX-5461 is currently in Phase I clinical trials for BRCA1/2 deficient tumors.
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