Journal
CHEMBIOCHEM
Volume 21, Issue 7, Pages 963-970Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201900534
Keywords
DNA damage; G-quadruplexes; ligand effects; site-specific binding; synthetic lethality
Funding
- Department of Science and Technology (DST)
- Department of Biotechnology (DBT)
- CSIR-India
- DST
- DBT-RA program in Biotechnology and Life Sciences
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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.
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