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

Sumirtha Balaratnam, Zachary R Torrey, David R Calabrese, Michael T Banco, Kamyar Yazdani, Xiao Liang, Christopher R Fullenkamp, Srinath Seshadri, Ronald J Holewinski, Thorkell Andresson, Adrian R Ferré-D'Amaré, Danny Incarnato, John S Schneekloth*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Neuroblastoma RAS (NRAS) is an oncogene that is deregulated and highly mutated in cancers including melanomas and acute myeloid leukemias. The 5' untranslated region (UTR) (5' 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' 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 5' UTRs to control translation remains a highly attractive strategy.

Original languageEnglish
Pages (from-to)643–657
Number of pages24
JournalCell Chemical Biology
Issue number6
Early online date30-May-2023
Publication statusPublished - 15-Jun-2023

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