Kirsten rat sarcoma virus oncogene homolog (KRAS) promoter polypyrimidine tract (KRAS PPT)

The KRAS promoter polypyrimidine tract is a regulatory DNA sequence located within the nuclease hypersensitive element (NHE) of the human KRAS gene (Kaiser et al., 2017, Biochemistry). This cytosine-rich region is capable of folding into a four-stranded non-canonical DNA structure known as an i-motif, which exists in equilibrium with a duplex and potentially a G-quadruplex on the complementary strand (Brooks et al., 2010, JBC). KRAS is a potent oncogene, and its overexpression or mutation is a primary driver in aggressive cancers such as pancreatic ductal adenocarcinoma and colorectal cancer (Sutherland et al., 2016, NAR). By targeting the polypyrimidine tract with small molecules that stabilize the i-motif structure, researchers aim to physically obstruct the binding of transcription factors like MAZ and hnRNP K, thereby silencing KRAS transcription (Cogoi et al., 2014, J. Med. Chem.). This transcriptional targeting strategy is particularly valuable because KRAS has historically been considered undruggable at the protein level due to its smooth surface and high affinity for GTP (Hurley et al., 2019, Annu. Rev. Pharmacol. Toxicol.). Experimental compounds such as IMC-158 have shown promise in selectively binding these structures to reduce KRAS mRNA and protein levels in cancer cell lines (Kaiser et al., 2017).

Other names

KRAS nuclease hypersensitive elementKRAS NHEKRAS i-motifKRAS promoter cytosine-rich tractKRAS mid-promoter polypyrimidine tract

Stabilization of non-canonical DNA structures (i-motifs) within the promoter region to inhibit transcription factor binding and downregulate gene expression (Kaiser et al., 2017, Biochemistry).