G-quadruplex ligand-mediated CHK1 and ERα suppression in endocrine-sensitive and endocrine-resistant luminal breast cancer cells

G-quadruplex (G4)-stabilizing ligands are promising tools for inhibiting tumor cell growth in both in vitro and in vivo models. G4 stabilization interferes with DNA replication, leading to replication stress (RS) and DNA damage, and affects gene expression. Clinical development of the telomere-targeting G4 ligand RHPS4 was discontinued due to cardiotoxicity, prompting the synthesis of congeners with retained activity and improved toxicological profiles. In this study, the antiproliferative effects of RHPS4 derivatives were tested in breast cancer cell lines, MCF7, MDA-MB-231, and HCC1937, and compared with non-tumorigenic breast epithelial cells and normal fibroblasts. Among the analogues, compound 190 preferentially inhibited proliferation in MCF7 cells, an effect weakly associated with telomeric DNA damage. Similar to RHPS4, compound 190 induced RS, downregulated CHK1, and reduced ESR1 mRNA and ERα protein levels in a dose-dependent manner. Reduced transcript levels and enhanced ERα degradation support contributions from both transcriptional and post-translational mechanisms, with degradation potentially linked to RS. These effects were also confirmed in endocrine-resistant MCF7-Y537S cells. Together, these findings identify CHK1 and ERα suppression as responses to compound 190 and support further investigation of acridine-based G4 ligands in endocrine-sensitive and endocrine-resistant luminal breast cancer.