Investigating the NRAS 5' UTR as a target for small molecules.

Publication Type:

Journal Article


Cell Chem Biol, Volume 30, Issue 6, p.643-657.e8 (2023)


5' Untranslated Regions, Cell Line, G-Quadruplexes, GTP Phosphohydrolases, Humans, Membrane Proteins, Neuroblastoma, RNA, Messenger


<p>Neuroblastoma RAS (NRAS) is an oncogene that is deregulated and highly mutated in cancers including melanomas and acute myeloid leukemias. The 5&#39; untranslated region (UTR) (5&#39; UTR) of the NRAS mRNA contains a G-quadruplex (G4) that regulates translation. Here we report a novel class of small molecule that binds to the G4 structure located in the 5&#39; UTR of the NRAS mRNA. We used a small molecule microarray screen to identify molecules that selectively bind to the NRAS-G4 with submicromolar affinity. One compound inhibits the translation of NRAS in&nbsp;vitro but showed only moderate effects on the NRAS levels in cellulo. Rapid Amplification of cDNA Ends and RT-PCR analysis revealed that the predominant NRAS transcript does not possess the G4 structure. Thus, although NRAS transcripts lack a G4 in many cell lines the concept of targeting folded regions within 5&#39; UTRs to control translation remains a highly attractive strategy.</p>