KRAS promoter G-quadruplex DNA (KRAS G4) (KRAS G4)

The KRAS promoter G-quadruplex DNA is a non-canonical secondary structure formed within the guanine-rich nuclease hypersensitive element (NHE) of the KRAS gene promoter (Cogoi & Xodo, 2006). This structure serves as a molecular switch that regulates the transcription of the KRAS oncogene, a key driver in many human cancers including pancreatic, colorectal, and lung carcinomas (Brooks et al., 2010). In its folded state, the G-quadruplex physically impedes the transcriptional machinery, thereby reducing the production of KRAS mRNA and protein (Kuo et al., 2015). Because the KRAS protein has historically been considered difficult to target directly due to its smooth surface and high affinity for GTP, targeting the G-quadruplex structure in its promoter offers an alternative therapeutic strategy to downregulate its expression (Ou et al., 2014). Small-molecule ligands, such as TMPyP4 and various indoloalkane derivatives, have been developed to bind and stabilize this structure, effectively silencing the gene in experimental models (Cogoi & Xodo, 2006). However, achieving high selectivity for the KRAS G-quadruplex over other genomic G-quadruplexes remains a significant challenge in clinical development (Brooks et al., 2010).

Other names

KRAS G4KRAS promoter G-quadruplexKRAS nuclease hypersensitive elementKRAS NHE

Small molecule ligands bind to and stabilize the G-quadruplex structure within the KRAS promoter region, which physically obstructs the transcriptional machinery and reduces the expression of the KRAS protein.