The G-quadruplex ligand CX-5461: an innovative candidate for disease treatment

Abstract

The ribosomal DNA (rDNA) plays a vital role in regulating protein synthesis by ribosome biogenesis, essential for maintaining cellular growth, metabolism, and more. Cancer cells show a high dependence on ribosome biogenesis and exhibit elevated rDNA transcriptional activity. CX-5461, also known as Pidnarulex, is a First-in-Class anticancer drug that has received 'Fast Track Designation' approval from the FDA. Initially reported to inhibit Pol I-driven rDNA transcription, CX-5461 was recently identified as a G-quadruplex structure (G4) stabilizer and is currently completed or undergoing multiple Phase I clinical trials in patients with breast and ovarian cancers harboring BRCA1/2, PALB2, or other DNA repair deficiencies. Additionally, preclinical studies have confirmed that CX-5461 demonstrates promising therapeutic effects against multifarious non-cancer diseases, including viral infections, and autoimmune diseases. This review summarizes the mechanisms of CX-5461, including its transcriptional inhibition of rDNA, binding to G4, and toxicity towards topoisomerase, along with its research status and therapeutic effects across various diseases. Lastly, this review highlights the targeted therapy strategy of CX-5461 based on nanomedicine delivery, particularly the drug delivery utilizing the nucleic acid aptamer AS1411, which contains a G4 motif to specifically target the highly expressed nucleolin on the surface of tumor cell membranes; It also anticipates the strategy of coupling CX-5461 with peptide nucleic acids and locked nucleic acids to achieve dual targeting, thereby realizing individualized G4-targeting by CX-5461. This review aims to provide a general overview of the progress of CX-5461 in recent years and suggest potential strategies for disease treatment involving ribosomal RNA synthesis, G4, and topoisomerase.

Keywords: CX-5461; Cancer; G-quadruplex; Ribosomal RNA; Ribosome biogenesis; Targeted therapy.

Fig. 1

The molecular mechanism of CX-5461 in inhibiting rDNA transcription and ribosome biogenesis in cancer and its potential impact on tumor cells. CX-5461 can disrupt the interaction between the SL1 complex within the RNA Pol I complex and the rDNA promoter, resulting in an unproductive mode of RNA Pol I by impeding the release of the RNA Pol I-Rrn3 complex from the rDNA promoter, poison TOP II, stabilize G4s in the rDNA promoter, and induce R-loop formation. This regulation affects multiple pathways, including the ATR/ATM signal, RPL5/RPL11-MDM2-p53 signal, cGAS-STING pathway, and Wnt/β-catenin pathway, ultimately leading to cell cycle arrest, cell senescence, autophagy, and apoptosis

Fig. 2

The impact of CX-5461 on the DNA transaction processes by binding and stabilizing G4 in the genome

Fig. 3

CX-5461 triggers TOP2-mediated DNA DSBs at transcription sites dependent on G4. In the model, the interaction of CX-5461 with G4 is facilitated by DNA topological stress provoked by RNA-Pol-dependent transcription that can be neutralized by TOP I; G4 stabilization by CX-5461 in transcription loci would give rise to unremitting RNA-Pol stasis, mobilizing TOP to settle the topological stress, and that TOP II may be poisoned at the transcribed region bearing G4

Fig. 4

The potential nano-delivery strategies of CX-5461. A Schematic representation of CX-5461, Cu-CX-5461, and DMPC/Chol-Cu-CX-5461; DMPC/Chol-Cu-CX-5461 at neutral pH can enhance the apparent solubility of CX5461 by over 500-fold and improve anti-tumor effects. B Illustration of the Sophora Flavescens-derived exosome-like nanovesicles (SFELNVs@CX5461) carrying CX5461 with other functional components. C Schematic diagram of the multifunctional nano-delivery system based on tetrahedral DNA (TDN) for transporting the G4 ligand. The G4 ligand achieves nano-delivery by binding to the G4 structures formed on the TDN (particularly the G4s formed by the DNA aptamer AS1411), and this delivery system recognizes the highly expressed nucleolin on the surface of tumor cell membranes via the G4 structure, facilitating active targeting of tumor cells. D Structural diagram of the nano-delivery system based on mesoporous silica nanoparticles (MSNs) for delivering CX-5461, named MSNs-CX-5461@PDA-PEG-APt, which utilizes AS1411, polyethylene glycol (PEG), and polydopamine (PDA), achieving high stability, a high loading capacity of CX-5461, and active targeting of tumor cells

Fig. 5

Preconceived individualized G4-targeting strategies of CX-5461 conjugated with oligonucleotide or its analogs (peptide nucleic acids, locked nucleic acids, etc.)