Targeting Oncogene Promoters and Ribosomal RNA Biogenesis by G-Quadruplex Binding Ligands Translate to Anticancer...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biochemistry

Background:

• G-quadruplex (GQ) structures are crucial in cancer gene regulation and represent promising therapeutic targets.
• Carbazole-based compounds offer potential for selective targeting of these structures.

Purpose of the Study:

• To investigate the structure-activity relationship of novel carbazole-based monocyanine ligands.
• To evaluate their binding affinity and selectivity towards oncogenic G-quadruplex DNA (e.g., c-MYC, BCL-2).
• To assess their therapeutic potential in inhibiting cancer cell proliferation via gene transcription and rRNA biogenesis interference.

Main Methods:

• Synthesis and characterization of carbazole-based monocyanine ligands with varying acceptor moieties (benzothiazole, lepidine, quinaldine).
• G-quadruplex binding studies using fluorescence spectroscopy and isothermal titration calorimetry (ITC).
• In vitro assays including dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), confocal microscopy, and rRNA biogenesis assessment.

Main Results:

• All synthesized ligands exhibited selective turn-on fluorescence upon binding to G-quadruplexes over duplex DNA.
• Ligands TCZ and TCA showed selective binding to c-MYC and BCL-2 GQs, respectively, through distinct interaction modes.
• The ligands effectively inhibited transcription of c-MYC and BCL-2, disrupted transcription factor binding, and induced nucleolar stress.
• Inhibition of Nucleolin occupancy at rDNA promoters led to arrested rRNA biogenesis, demonstrating a dual inhibitory mechanism.

Conclusions:

• Carbazole-based monocyanine ligands are effective in targeting oncogenic G-quadruplexes, offering a dual therapeutic approach.
• These ligands selectively inhibit key oncogenic pathways (c-MYC, BCL-2) and rRNA biogenesis, leading to synergistic anticancer effects.
• The turn-on fluorescence property enables real-time monitoring of GQ interactions and cellular localization, facilitating drug development.