Investigating the NRAS 5′ UTR as a target for small molecules

Neuroblastoma RAS (NRAS) is an oncogene that is deregulated and highly mutated in cancers including melanomas and acute myeloid leukemias. The 50 untranslated region (UTR) (50 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 50 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 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 50 UTRs to control translation remains a highly attractive strategy.

Automated summary

Neuroblastoma RAS (NRAS) is an oncogene highly mutated in various cancers. A new class of small molecules that selectively bind to the G-quadruplex structure in the 50 untranslated region (UTR) of NRAS mRNA has been discovered. These molecules can inhibit the translation of NRAS in vitro, suggesting the potential of targeting folded regions within 50 UTRs for translation control.