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

Abstract

Deadly interactions: Ligand 1 inhibits c-MYC and BCL2 expression by stabilizing their promoter quadruplexes; this leads to S-phase arrest, DNA damage, and apoptosis by synthetic lethal interaction in MCF-7 cells. Herein, a prolinamide-derived peptidomimetic that preferentially binds to c-MYC and BCL2 G-quadruplexes present in the promoter regions of apoptosis-related genes (c-MYC and BCL2) over other DNA quadruplexes are described. Biological assays, such as real-time quantitative reverse transcription, western blot, dual luciferase, and small interfering RNA knockdown assays, indicate that the ligand triggers a synthetic lethal interaction by simultaneously inhibiting the expression of c-MYC and BCL2 genes through their promoter G-quadruplexes. The ligand shows antiproliferative activity in MCF-7 cells that overexpress both MYC and BCL2 genes, in comparison to cells that overexpress either of the two. Moreover, the ligand induces S-phase cell-cycle arrest, DNA damage, and apoptosis in MCF-7 cells.