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

Autor:	Balaratnam S; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA., Torrey ZR; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA., Calabrese DR; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA., Banco MT; Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA., Yazdani K; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA., Liang X; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA., Fullenkamp CR; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA., Seshadri S; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA., Holewinski RJ; Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA., Andresson T; Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA., Ferré-D'Amaré AR; Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA., Incarnato D; Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, the Netherlands., Schneekloth JS Jr; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA. Electronic address: schneeklothjs@mail.nih.gov.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2023 Jun 15; Vol. 30 (6), pp. 643-657.e8. Date of Electronic Publication: 2023 May 30.
DOI:	10.1016/j.chembiol.2023.05.004
Abstrakt:	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. Competing Interests: Author contributions S.B., Z.R.T., D.R.C., K.Y., X.L., C.R.F., and S.S. performed screening, biochemical, biological, and synthetic chemistry experiments described in the manuscript and helped write/edit the manuscript. M.B. performed X-ray crystallographic experiments and helped edit the manuscript. R.J.H. and T.A. performed and analyzed proteomics assays. A.R.F. edited the manuscript. D.I. performed SHAPE and CAGE experiments and edited the manuscript. J.S.S. conceived experiments and wrote/edited the manuscript. Declaration of interests The authors declare no competing interests. (Copyright © 2023. Published by Elsevier Ltd.)
Databáze:	MEDLINE
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