Design, Synthesis, and Evaluation of Novel <i>p</i>-(Methylthio)styryl Substituted Quindoline Derivatives as Neuroblastoma RAS (NRAS) Repressors via Specific Stabilizing the RNA G-Quadruplex

Wang, Peng; Sun, Zhongguo; Zhang, Qi; Cheng, Sui-Qi; Wang, Shi-Ke; Wang, Xiaona; Kuang, Guotao; Su, Xiao-Xuan; Tan, Jia‐Heng; Huang, Zhi‐Shu; Ou, Tian‐Miao

doi:10.1021/acs.jmedchem.8b00257

Cited by 33 publications

(16 citation statements)

References 60 publications

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“…After them, several compounds with this ability were discovered. Both a polyaromatic molecule, RGB-1 [161], and a novel p-(methylthio)styryl-substituted quindoline derivative [160], stabilize n-RAS G4 and subsequently repress n-RAS translation. An anionic phthalocyanine, ZnAPC, is another G4 ligand that even binds to n-RAS in the presence of abundant RNA in mammalian cells, resulting in selective cleavage of the targeted G4 upon photo-irradiation [167].…”

Section: Rna G4 Ligandsmentioning

confidence: 99%

Quadruplex Ligands in Cancer Therapy

Sánchez-Martín

Soriano

García‐Salcedo

2021

Cancers

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Nucleic acids can adopt alternative secondary conformations including four-stranded structures known as quadruplexes. To date, quadruplexes have been demonstrated to exist both in human chromatin DNA and RNA. In particular, quadruplexes are found in guanine-rich sequences constituting G-quadruplexes, and in cytosine-rich sequences forming i-Motifs as a counterpart. Quadruplexes are associated with key biological processes ranging from transcription and translation of several oncogenes and tumor suppressors to telomeres maintenance and genome instability. In this context, quadruplexes have prompted investigations on their possible role in cancer biology and the evaluation of small-molecule ligands as potential therapeutic agents. This review aims to provide an updated close-up view of the literature on quadruplex ligands in cancer therapy, by grouping together ligands for DNA and RNA G-quadruplexes and DNA i-Motifs.

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Section: Rna G4 Ligandsmentioning

confidence: 99%

Quadruplex Ligands in Cancer Therapy

Sánchez-Martín

Soriano

García‐Salcedo

2021

Cancers

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“…Thus, stabilization of the NRAS-G4 represents an opportunity for pharmacological suppression of NRAS expression with small molecule ligands. The development of a few small molecule stabilizers for NRAS-G4 has been reported in recent years, though selectivity remains a challenge [41][42] .…”

Section: Introductionmentioning

confidence: 99%

Investigating the NRAS 5’ UTR as a Target for Small Molecules

Balaratnam

Torrey

Calabrese

et al. 2022

Preprint

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Neuroblastoma RAS (NRAS) is an oncogene that is deregulated and highly mutated in cancers including melanomas and acute myeloid leukemias. Constitutively activated NRAS induces the MAPK and AKT signaling pathways and leads to uncontrolled proliferation and cell growth, making it an attractive target for small molecule inhibition. Like all RAS-family proteins, it has proven difficult to identify small molecules that directly inhibit the protein. An alternative approach would involve targeting the NRAS mRNA. The 5′ untranslated region (5′ UTR) of the NRAS mRNA is reported to contain a G-quadruplex (G4) that regulates translation of NRAS mRNA. Stabilizing the G4 structure with small molecules could reduce NRAS protein expression in cancer cells by impacting 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 (SMM) screen to identify molecules that selectively bind to the NRAS-G4. Biophysical studies demonstrated that compound 18 binds reversibly to the NRAS-G4 structure with submicromolar affinity. A Luciferase based reporter assay indicated that 18 inhibits the translation of NRAS via stabilizing the NRAS-G4 in vitro but showed only moderate effects on the NRAS levels in cellulo. Rapid Amplification of cDNA Ends (RACE), RT-PCR analysis on 14 different NRAS-expressing cell lines, coupled with analysis of publicly available CAGE seq experiments, revealed that predominant NRAS transcript does not possess the G4 structure. Further analysis of published rG4 and G4 sequencing data indicated the presence of G4 structure in the promoter region of NRAS gene (DNA) but not in the mRNA. Thus, although many NRAS transcripts lack a G4 in many cell lines the broader concept of targeting folded regions within 5' UTRs to control translation remains a highly attractive strategy and this work represents an intriguing example of transcript heterogeneity impacting targetability.

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“…In particular, numerous small molecules such as anilinoquinazoline, quindoline, carbazole, acridone, phenanthroline, curcumin, and their analogs have been identified, which bind and stabilize the c-myc G4 motif. As a result, the transcription and translation activity of c-myc gene get downregulated 54 , 62 – 65 . Additionally, water-soluble dyes have also shown strong interaction with c-myc G4 as fluorescence probes 66 , 67 .…”

Section: Introductionmentioning

confidence: 99%

Piperine analogs arrest c-myc gene leading to downregulation of transcription for targeting cancer

Pandya

Kumar

2021

Sci Rep

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G-quadruplex (G4) structures are considered a promising therapeutic target in cancer. Since Ayurveda, Piperine has been known for its medicinal properties. Piperine shows anticancer properties by stabilizing the G4 motif present upstream of the c-myc gene. This gene belongs to a group of proto-oncogenes, and its aberrant transcription drives tumorigenesis. The transcriptional regulation of the c-myc gene is an interesting approach for anticancer drug design. The present study employed a chemical similarity approach to identify Piperine similar compounds and analyzed their interaction with cancer-associated G-quadruplex motifs. Among all Piperine analogs, PIP-2 exhibited strong selectivity, specificity, and affinity towards c-myc G4 DNA as elaborated through biophysical studies such as fluorescence emission, isothermal calorimetry, and circular dichroism. Moreover, our biophysical observations are supported by molecular dynamics analysis and cellular-based studies. Our study showed that PIP-2 showed higher toxicity against the A549 lung cancer cell line but lower toxicity towards normal HEK 293 cells, indicating increased efficacy of the drug at the cellular level. Biological evaluation assays such as TFP reporter assay, quantitative real-time PCR (qRT- PCR), and western blotting suggest that the Piperine analog-2 (PIP-2) stabilizes the G-quadruplex motif located at the promoter site of c-myc oncogene and downregulates its expression. In conclusion, Piperine analog PIP-2 may be used as anticancer therapeutics as it affects the c-myc oncogene expression via G-quadruplex mediated mechanism.

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Design, Synthesis, and Evaluation of Novel p-(Methylthio)styryl Substituted Quindoline Derivatives as Neuroblastoma RAS (NRAS) Repressors via Specific Stabilizing the RNA G-Quadruplex

Cited by 33 publications

References 60 publications

Quadruplex Ligands in Cancer Therapy

Quadruplex Ligands in Cancer Therapy

Investigating the NRAS 5’ UTR as a Target for Small Molecules

Piperine analogs arrest c-myc gene leading to downregulation of transcription for targeting cancer

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