Dual Transcriptional Repression of Oncogenic <i>c-KIT</i> and <i>KRAS</i> 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, <b>TI12</b>, which induces synthetic lethality in K562 leukemia cells by preferentially targeting G-quadruplexes (G4s) in the promoter regions of <i>c-KIT1</i> and <i>KRAS</i>. Among a series of synthesized triazolyl-indole derivatives, <b>TI12</b> exhibits submicromolar affinity for these G4s, as confirmed by biophysical assays along with molecular docking and simulations. Biological studies demonstrate that <b>TI12</b> represses <i>c-KIT</i> and <i>KRAS</i> transcription, leading to G1-phase cell cycle arrest, ROS-mediated DNA damage, and apoptosis. Notably, <b>TI12</b> does not affect cells overexpressing either <i>c-KIT</i> or <i>KRAS</i>, suggesting that its cytotoxicity arises from the simultaneous suppression of both oncogenes. <i>In vivo</i> studies depicted the potential antitumor efficacy of <b>TI12</b> 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.