In 10-15% of
cancers, telomere maintenance is provided by a
telomerase-independent mechanism known as alternative lengthening of telomere (ALT), making
telomerase inhibitors ineffective on these
cancers.
Ligands that stabilize telomeric G-quadruplex (G4) are considered to be able to inhibit either the ALT process or disrupt the T-loop structure, which would be promising therapeutic agents for ALT
cancers. Notably, the 3'-terminal overhang of telomeric
DNA might fold into multimeric G4 containing consecutive G4 subunits, which offers an attractive target for selective
ligands considering large numbers of G4s widespread in the genome. In this study, a dimeric aryl-substituted
imidazole (DIZ-3) was developed as a selective multimeric G4
ligand based on a G4-ligand-dimerizing strategy. Biophysical experiments revealed that DIZ-3 intercalated into the G4-G4 interface, stabilizing the higher-order structure. Furthermore, this
ligand was demonstrated to induce cell cycle arrest and apoptosis, and thus inhibited cell proliferation in an ALT
cancer cell line.
Cancer cells were more sensitive to DIZ-3, relative to normal cells. Notably, DIZ-3 had little effect on the transcription of several G4-dependent oncogenes. This study provides a nice example for discovering dimeric agents to potentially treat ALT
cancers via targeting telomeric multimeric G4.