# Thiazole peptidomimetics as chemical modulators of KRAS gene expression via G-quadruplex stabilization

## TL;DR

Researchers developed a compound that targets the KRAS gene by stabilizing its DNA structure, reducing cancer-related signaling and offering a new approach to treat hard-to-drug cancers.

## Contribution

A novel bis-thiazole peptidomimetic is shown to selectively stabilize the KRAS G-quadruplex, leading to oncogene downregulation.

## Key findings

- TTh2 selectively binds and stabilizes the KRAS promoter G-quadruplex structure.
- KRAS mRNA and protein levels are significantly suppressed in HeLa cells.
- Downstream signaling pathways MAPK and Akt/mTOR are inhibited by TTh2 treatment.

## Abstract

KRAS 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 KRAS G-quadruplex structure, resulting in marked suppression of the KRAS 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.

Bis-thiazole peptidomimetic TTh2 selectively binds and stabilizes the KRAS promoter G-quadruplex, leading to KRAS downregulation and inhibition of MAPK and Akt/mTOR pathways, demonstrating a novel strategy for targeting ''undruggable'' oncogenes.