CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours
University of British Columbia · University of Cambridge · +9 more institutions
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…
Citation impact
- FWCI
- 19.96
- Percentile
- 100%
- References
- 55
Authors
39Topics & keywords
- DNA damage
- DNA repair
- DNA
- Cancer research
- Biology
- G-quadruplex
- Synthetic lethality
- Chemistry
- Good health and well-being