Dual Transcriptional Repression of Oncogenic c-KIT and KRAS by G4-Targeting Triazolyl-Indole Scaffolds Induces Synthetic Lethality in Leukemia Cells.

In this study, we report the design and synthesis of a triazolyl-indole derivative, TI12, which induces synthetic lethality in K562 leukemia cells by preferentially targeting G-quadruplexes (G4s) in the promoter regions of c-KIT1 and KRAS. Among a series of synthesized triazolyl-indole derivatives, TI12 exhibits submicromolar affinity for these G4s, as confirmed by biophysical assays along with molecular docking and simulations. Biological studies demonstrate that TI12 represses c-KIT and KRAS transcription, leading to G1-phase cell cycle arrest, ROS-mediated DNA damage, and apoptosis. Notably, TI12 does not affect cells overexpressing either c-KIT or KRAS, suggesting that its cytotoxicity arises from the simultaneous suppression of both oncogenes. In vivo studies depicted the potential antitumor efficacy of TI12 with minimal systemic toxicity. This study highlights the potential of G4-targeting ligands as synthetic lethal agents, offering a novel strategy for disrupting cooperative oncogenic pathways in leukemia.