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

doi:10.1016/j.chembiol.2023.05.004

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

Molecular Genetics

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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 language	English
Pages (from-to)	643–657
Number of pages	24
Journal	Cell Chemical Biology
Volume	30
Issue number	6
Early online date	30-May-2023
DOIs	https://doi.org/10.1016/j.chembiol.2023.05.004
Publication status	Published - 15-Jun-2023

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Investigating the NRAS 5′ UTR as a target for small moleculesFinal publisher's version, 6.5 MBLicence: Taverne

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Balaratnam, S., Torrey, Z. R., Calabrese, D. R., Banco, M. T., Yazdani, K., Liang, X., Fullenkamp, C. R., Seshadri, S., Holewinski, R. J., Andresson, T., Ferré-D'Amaré, A. R., Incarnato, D., & Schneekloth, J. S. (2023). Investigating the NRAS 5' UTR as a target for small molecules. Cell Chemical Biology, 30(6), 643–657. https://doi.org/10.1016/j.chembiol.2023.05.004

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title = "Investigating the NRAS 5' UTR as a target for small molecules",

abstract = "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.",

author = "Sumirtha Balaratnam and Torrey, {Zachary R} and Calabrese, {David R} and Banco, {Michael T} and Kamyar Yazdani and Xiao Liang and Fullenkamp, {Christopher R} and Srinath Seshadri and Holewinski, {Ronald J} and Thorkell Andresson and Ferr{\'e}-D'Amar{\'e}, {Adrian R} and Danny Incarnato and Schneekloth, {John S}",

note = "Copyright {\textcopyright} 2023. Published by Elsevier Ltd.",

year = "2023",

month = jun,

day = "15",

doi = "10.1016/j.chembiol.2023.05.004",

language = "English",

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pages = "643–657",

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T1 - Investigating the NRAS 5' UTR as a target for small molecules

AU - Balaratnam, Sumirtha

AU - Torrey, Zachary R

AU - Calabrese, David R

AU - Banco, Michael T

AU - Yazdani, Kamyar

AU - Liang, Xiao

AU - Fullenkamp, Christopher R

AU - Seshadri, Srinath

AU - Holewinski, Ronald J

AU - Andresson, Thorkell

AU - Ferré-D'Amaré, Adrian R

AU - Incarnato, Danny

AU - Schneekloth, John S

PY - 2023/6/15

Y1 - 2023/6/15

N2 - 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.

AB - 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.

U2 - 10.1016/j.chembiol.2023.05.004

DO - 10.1016/j.chembiol.2023.05.004

M3 - Article

C2 - 37257453

SN - 2451-9448

VL - 30

SP - 643

EP - 657

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 6

ER -

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

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