A first-in-class clinical G-quadruplex-targeting drug. The bench-to-bedside translation of the fluoroquinolone QQ58 to CX-5461 (Pidnarulex)
Abstract
CX-3543 (Quarfloxin) and CX-5461 (Pidnarulex) were originally derived from a group of fluoroquinolones that were shown to have dual topoisomerase II (Top2) and G-quadruplex (G4) interactions, and QQ58 was the starting structure for their design. Quarfloxin was initially shown to inhibit c-MYC mRNA expression. Studies at Cylene Pharmaceuticals showed that the primary mechanism of action of Quarfloxin is due to displacement of nucleolin from quadruplexes on the non-template strand of rDNA, causing rapid redistribution of nucleolin from nucleoli, inhibition of rRNA synthesis, and apoptotic death in cancer cells. At Cylene a follow-up compound to Quarfloxin, named Pidnarulex (CX-5461), was optimized for targeting RNA Pol 1. Significantly, in more recent work published in Proc Natl Acad Sci USA and Cell in 2020 and in eLIFE and Nat Comm in 2021, it has been shown that the real molecular target for Pidnarulex is Top2 at transcribed regions containing G4s, rather than RNA Pol 1. These results support the original design strategy published in Mol Cancer Ther in 2001, which was to rationally design a G4-targeting drug (QQ58) starting from a fluoroquinolone duplex-targeting Top2 poison (A-62176) that had good drug-like properties. A very important breakthrough was realized when homologous recombination (HR) was found to be important in the repair of DNA damage caused by G4-interactive compounds, suggesting that a synthetic lethal approach might be useful in identifying cancer patients…
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The therapeutic efficacy of CX-5461 may largely rely on the induction of genomic instability and a compromised DNA damage response.
“suggesting that the therapeutic efficacy of CX-5461 may largely rely on the induction of genomic instability and a compromised DNA damage response (92).”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [92]
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- Authors
- Xu, H., & Hurley, L. H.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Xu, Hong
- Hurley, Laurence H.
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 77
- Pages
- 129016
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W4300773325
- Cited by
- 84
- References
- 0
- Citations by year
- 2026: 24 · 2025: 12 · 2024: 29 · 2023: 16 · 2022: 3
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA236350)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
- Keywords
- CX-5461, fluoroquinolones, G-quadruplex stabilization, topoisomerase II, nucleolin, ribosomal DNA, RNA polymerase I, synthetic lethality, BRCA mutations, homologous recombination, non-homologous end joining, DNA repair, breast cancer, ovarian cancer
- MeSH terms
- Canada, DNA Topoisomerases, Type II, DNA Repair, Enzyme Inhibitors, Humans, Naphthyridines, RNA, Fluoroquinolones, Benzothiazoles
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