Thiazole peptidomimetics as chemical modulators of <i>KRAS</i> gene expression <i>via</i> G-quadruplex stabilization

<i>KRAS</i> is one of the most frequently mutated oncogenes in human cancers and remains a challenging target for therapeutic intervention, often labeled "undruggable." We herein synthesized triazole-containing peptidomimetics TTh1 and TTh2, to explore their selective interactions with DNA quadruplexes. Biophysical studies reveal that TTh2 with a prolinamide motif selectively binds to and stabilizes the <i>KRAS</i> G-quadruplex structure, resulting in marked suppression of the <i>KRAS</i> mRNA and protein levels in HeLa cells. This downregulation correlates with the inhibition of key downstream signaling pathways, including MAPK and Akt/mTOR, which are critical for cancer cell proliferation and survival. These results highlight the potential of G4-binding peptidomimetics as chemical tools for modulating oncogene expression through selective stabilization of promoter G-quadruplex structures.