Abstract 3057: Telomerase and G-quadruplex dual-targeting chimera inhibits melanoma via telomere disruption

Abstract Interference with telomerase and telomere maintenance have historically been viewed as a highly attractive target for anticancer therapies by restraining proliferative capacity via telomere length. A range of screens have identified many small molecule inhibitors of telomerase, but these inhibitors have all encountered obstacles in the early stages of preclinical studies primarily due to their limited potency and delayed onset of cytotoxic effects. Ligand-induced stabilization of telomeric G-quadruplexes (G4s) formation have been thought to be negative regulators of telomerase activity. However, given that G4-forming sequences are pervasive in human genome, G4 ligands display quite limited intra-G4 selectivity, resulting in a risk of side effects in therapeutic use. Here, we introduce an innovative telomere targeting strategy leveraging telomerase and G4 dual-targeting chimera. We design and synthesize such chimera by connecting telomerase inhibitor BIBR1532 to G4 ligands pyridostatin via a linker. On one hand, pyridostatin can enhance the anticancer potency of BIBR1532 by targeting telomere G4 structures. On the other hand, BIBR1532 can recruit pyridostatin to the telomere region by directly interacting with telomerase, thereby mitigating its off-target effects. As expected, the chimeric compound is capable of telomerase inhibition and suppress melanoma progression in vitro and in patient-derived xenograft (PDX) model with no observable toxicity. Notably, the anti-melanoma effects of the chimeric compound outperform that of BIBR1532 or pyridostatin alone. Our study provides a more effective strategy for telomerase inhibition, and the telomerase and G4 dual-targeting chimera is a promising candidate for anticancer therapy. Citation Format: Yutong Sui, qi xu, mingsheng liu, jinyu liu, geng qin. Telomerase and G-quadruplex dual-targeting chimera inhibits melanoma via telomere disruption [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3057.