Novel phenanthrene imidazoles as telomeric G-quadruplex ligands trigger potent immunogenic cell death in triple-negative breast cancer

In this study, we rationally designed and synthesized a series of novel phenanthrene imidazoles targeting telomeric G4. Among them, PI-2 was identified as the most promising ligand with high cytotoxicity, cellular uptake efficiency and G4-interacting ability. Cellular studies indicated that PI-2 inhibited the proliferation and migration of both human and mouse triple-negative breast cancer (TNBC) cells. PI-2 triggered the occurrence of DDR and ICD, where the related pathways were further decided. In vivo experiments displayed that PI-2-treated dying cells could be an effective vaccination to reduce tumor burden and promote the infiltration of CD8+ and CD4+ T cells to the tumor microenvironment (TME). To our knowledge, it is the first time to report a DDR-targeted G4 ligand with ICD-inducing ability in immunocompetent animals, which may provide new insights for the development of promising G4-based immunochemotherapeutic agents.PMID:37524278 | DOI:10.1016/j.ijbiomac.2023.126068
Source: International Journal of Biological Macromolecules - Category: Biochemistry Authors: Source Type: research