Kirsten rat sarcoma virus oncogene homolog RNA G-quadruplex (KRAS rG4)

The Kirsten rat sarcoma virus oncogene homolog (KRAS) RNA G-quadruplex (rG4) is a non-canonical secondary structure formed within the guanine-rich 5' untranslated region (5' UTR) of the KRAS messenger RNA. KRAS is a critical GTPase in the MAPK/ERK and PI3K/Akt signaling pathways, and its mutation is a primary driver in many aggressive malignancies, including pancreatic and lung cancers (Cogoi et al., 2010, PMID: 20925232). The rG4 structure serves as a natural translational 'brake' that regulates the expression of the KRAS protein; however, in cancer cells, this regulation is often insufficient to prevent oncogenic signaling. Therapeutic strategies currently focus on identifying small-molecule stabilizers, such as naphthalene diimide derivatives (e.g., CM03), or specific aptamers (e.g., SYL3C) that lock the rG4 structure in a stable conformation to sterically hinder the ribosome and downregulate KRAS protein synthesis (Xodo et al., 2018, PMID: 30121773). Targeting the KRAS RNA G-quadruplex offers a promising alternative to direct protein inhibition, potentially overcoming the 'undruggable' nature of certain KRAS variants by intervening at the post-transcriptional level (Cogoi et al., 2014, PMID: 24706562).

Other names

KRAS 5'-UTR G-quadruplexKRAS mRNA G-quadruplexKRAS rG4 structureK-ras RNA G-quadruplex

Small-molecule ligands or aptamers bind to and stabilize the G-quadruplex structure within the 5' untranslated region (5' UTR) of the KRAS mRNA, creating a physical barrier that inhibits the ribosomal machinery from initiating or continuing translation, thereby reducing KRAS protein levels.