Targeting G-Quadruplex DNA for Cancer Chemotherapy.
Curr Drug Discov Technol, 2022;19(3):e140222201110.
Debbarma S[1], Acharya PC[1]
Affiliations
PMID: 35156574DOI: 10.2174/1570163819666220214115408
Abstract
The self-association of DNA formed by Hoogsteen hydrogen bonding comprises several layers of four guanine or G-tetrads or G4s. The distinct feature of G4s, such as the G-tetrads and loops, qualify structure-selective recognition by small molecules and various ligands and can act as potential anticancer therapeutic molecules. The G4 selective ligands can influence gene expression by targeting a nucleic acid structure rather than sequence. Telomere G4 can be targeted for cancer treatment by small molecules inhibiting the telomerase activity, whereas c-MYC is capable of controlling transcription and can be targeted to influence transcription. The k-RAS is one of the most frequently encountered oncogenic driver mutations in pancreatic, colorectal, and lung cancers. The k-RAS oncogene plays an important role in acquiring and increasing drug resistance and can also be directly targeted by small molecules to combat k-RAS mutant tumors. Modular G4 ligands with different functional groups, side chains, and rotatable bonds, as well as conformation, affect the binding affinity/ selectivity in cancer chemotherapeutic interventions. These modular G4 ligands act by targeting the diversity of G4 loops and groves and assist in developing more drug-like compounds with selectivity. In this review, we present the recent research on synthetic G4 DNA-interacting ligands as an approach towards the discovery of target-specific anticancer chemotherapeutic agents.
Keywords: G-Quadruplex; anticancer G4 ligands; c-MYC; k-RAS; modular G4 ligand; telomerase inhibitors
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