Mr. Ka Hin Chan
Cancer is a leading cause of death worldwide. Among various cancers, several of the most commonly occurring mutations are the three members of the RAS family genes. These mutated genes express the mutated GTPases for abnormal cancer cell proliferation. Due to the structural features and signaling pathways of RAS proteins, the mutated RAS proteins are considered undruggable and thus no drug has been identified currently. Over the past decades, studies have revealed that nucleic acids consisting of guanine(G)-rich sequences can adopt a four-stranded structure, which is termed G-quadruplex (G4), and plays important roles in both gene and protein expression in cells. The mRNA of NRAS oncogenes also contains several G-rich regions that may form G4 structures. These mRNA G4s may provide alternative drug targets for their undruggable NRAS protein because its expression can be inhibited through targeting NRAS mRNA G4s with small-molecules. Herein, we reported a newly designed compound, B3C, which was found able to interact with NRAS mRNA G4s selectively. Both in vitro and cellular interactions between B3C and these mRNA G4s were confirmed in the present study. We also found that the compound markedly downregulated NRAS proteins and induced apoptosis in HeLa cells. The results obtained may illustrate that the use of ligands selectively targeting mRNA G4s of oncogenes such as NRAS may be a promising anticancer strategy. Our study provides novel insights on the development of RAS-related anticancer therapy.