G-Quadruplex-Binding Small Molecule Induces Synthetic Lethality in Breast Cancer Cells by Inhibiting c-MYC and BCL2...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Biology

Background:

• G-quadruplexes in gene promoters (c-MYC, BCL2) regulate apoptosis.
• Targeting these structures offers a novel therapeutic strategy.
• Simultaneous inhibition of c-MYC and BCL2 is a key goal in cancer therapy.

Purpose of the Study:

• To describe a prolinamide-derived peptidomimetic.
• To demonstrate its selective binding to c-MYC and BCL2 promoter G-quadruplexes.
• To evaluate its therapeutic potential in cancer cells.

Main Methods:

• Synthesis and characterization of the peptidomimetic ligand.
• G-quadruplex binding assays.
• Real-time quantitative reverse transcription, Western blot, and dual luciferase assays.
• Small interfering RNA (siRNA) knockdown assays.
• Antiproliferative assays in MCF-7 cells.
• Cell cycle analysis and DNA damage assessment.

Main Results:

• The peptidomimetic selectively binds to c-MYC and BCL2 G-quadruplexes.
• The ligand inhibits c-MYC and BCL2 gene expression via promoter G-quadruplexes, inducing synthetic lethality.
• Significant antiproliferative activity was observed in MCF-7 cells overexpressing both MYC and BCL2.
• The compound induced S-phase cell-cycle arrest, DNA damage, and apoptosis.

Conclusions:

• A novel peptidomimetic effectively targets c-MYC and BCL2 promoter G-quadruplexes.
• This dual inhibition strategy shows promise for cancer therapy by inducing synthetic lethality.
• The ligand demonstrates significant antiproliferative effects and induces apoptosis in relevant cancer models.