Drug-Like Small Molecules That Inhibit Expression of the Oncogenic MicroRNA-21

Shortridge, Matthew D.; Chaubey, Bhawna; Zhang, Huanyu J; Pavelitz, Thomas; Narayana, Vidadala V.; Tang, Chenghui; Olsen, Gregory L.; Calin, George A.; Varani, Gabriele

doi:10.1021/acschembio.2c00502

Cited by 9 publications

(13 citation statements)

References 68 publications

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“…A number of drug‐like small molecules bind specifically to the precursor of the oncogenic and pro‐inflammatory microRNA‐21 were reported by Varani and co‐workers in 2023 [65] . These anti‐proliferative activity ligands, an analogue 52 shown in Figure 7, exhibit strong binding activity with mid‐nanomolar affinity toward microRNA‐21 and induce distinctive structural changes in the RNA that is correlated with a specific inhibition of miRNA processing.…”

Section: Rna Structure‐targeting Small Molecule Ligands For Drug Disc...mentioning

confidence: 92%

“…A number of drug-like small molecules bind specifically to the precursor of the oncogenic and pro-inflammatory micro-RNA-21 were reported by Varani and co-workers in 2023. [65] These anti-proliferative activity ligands, an analogue 52 shown in Figure 7, exhibit strong binding activity with mid-nanomolar affinity toward microRNA-21 and induce distinctive structural changes in the RNA that is correlated with a specific inhibition of miRNA processing. In addition, the cellular proliferation and microRNA-21 levels in gastric adenocarcinoma (AGS) and pancreatic (ASPC1) cancer cells were reduced with the ligand while kinases or classical receptors were not inhibited.…”

Section: Rna Structure-targeting Small Molecule Ligands For Drug Disc...mentioning

confidence: 99%

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RNA‐Selective Small‐Molecule Ligands: Recent Advances in Live‐Cell Imaging and Drug Discovery

Chan,

Wang,

Zheng

et al. 2023

ChemMedChem

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RNA structures, including those formed from coding and noncoding RNAs, alternative to protein‐based drug targets, could be a promising target of small molecules for drug discovery against various human diseases, particularly in anticancer, antibacterial and antivirus development. The normal cellular activity of cells is critically dependent on the function of various RNA molecules generated from DNA transcription. Moreover, many studies support that mRNA‐targeting small molecules may regulate the synthesis of disease‐related proteins via the non‐covalent mRNA‐ligand interactions that do not involve gene modification. RNA‐ligand interaction is thus an attractive approach to address the challenge of “undruggable” proteins in drug discovery because the intracellular activity of these proteins is hard to be suppressed with small molecule ligands. We selectively surveyed a specific area of RNA structure‐selective small molecule ligands in fluorescence live cell imaging and drug discovery because the area was currently underexplored. This state‐of‐the‐art review thus mainly focuses on the research published within the past three years and aims to provide the most recent information on this research area; hopefully, it could be complementary to the previously reported reviews and give new insights into the future development on RNA‐specific small molecule ligands for live cell imaging and drug discovery.

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Section: Rna Structure‐targeting Small Molecule Ligands For Drug Disc...mentioning

confidence: 92%

Section: Rna Structure-targeting Small Molecule Ligands For Drug Disc...mentioning

confidence: 99%

RNA‐Selective Small‐Molecule Ligands: Recent Advances in Live‐Cell Imaging and Drug Discovery

Chan,

Wang,

Zheng

et al. 2023

ChemMedChem

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“…The expression and purification of human TRBP was based on previously described procedures (34,35). The pET28a-TRBP was purchased from Addgene (Addgene plasmid # 50351).…”

Section: Methodsmentioning

confidence: 99%

Use of steric blocking antisense oligonucleotides for the targeted inhibition of junction containing precursor microRNAs

Ma,

Howden,

Keane

2024

Preprint

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Antisense oligonucleotides (ASOs) are widely used as therapeutics for neurodegenerative diseases, cancers, and virus infections. One class of ASOs functions to enhance protein expression by sequestering the mature microRNA (miRNA) in a double-stranded structure within the RNA-induced silencing complex (RISC). An alternative approach for the targeted control of gene expression is to use ASOs that bind to the pre-elements of miRNAs (pre-miRNAs) and modulate their enzymatic processing. Here, we demonstrate that ASOs can be used to disrupt a specific structural feature, “junction,” within pre-miR-31 that is important in directing efficient processing by the Dicer/TRBP complex. Furthermore, we extend and validate this strategy to pre-miR-144, which has a similar junction-dependent structure-function relationship. We found that a significant number of human pre-miRNAs are predicted to contain junctions, and validated our ASO approach on several members of this group. Importantly, we also verified the application of junction-targeting ASOs for the specific inhibition of pre-miRNA processingin cell. Our study reemphasizes the important roles of RNA structure in regulating Dicer/TRBP processing of pre-miRNAs and provides the framework to develop structure-informed ASOs that serve to inhibit miRNA production.

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“…This mechanism of action (MOA) is responsible for the antiproliferative activities shown by synthetic compounds, which was also confirmed in gastric adenocarcinoma AGS and pancreatic ASPC1 cells. These compounds were evaluated for specificity and did not show any noticeable activity against other pre-miRNA, drug receptors, or kinases, as confirmed by the miRNA-binding and CEREP assays, respectively . Another miRNA involved in cancer, miR-372, works by downregulating large tumor-suppressor kinase 2 (LATS2) and has been explored as a drug target.…”

Section: Different Types Of Rnas As Small-molecule Targetsmentioning

confidence: 99%

“…Recently, compounds having the 2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[3,4-d]pyrimidin-4(3 H )-one structure were synthesized to selectively target the Dicer cleavage site in pre-miR-21 (PDB: 5UZZ). The binding of synthetic small molecules leads to the formation of 2 GU base pairs just above the “cut site” (Figure b). A nucleotide A29 within the target RNA, usually present in two conformations, bulged-out and stacked-in, transforms entirely into the bulged-out conformation, a form that represses the Dicer activity.…”

Section: Different Types Of Rnas As Small-molecule Targetsmentioning

confidence: 99%

RNA–Small-Molecule Interaction: Challenging the “Undruggable” Tag

Kaur,

Sharma,

Mundlia

et al. 2024

J. Med. Chem.

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RNA targeting, specifically with small molecules, is a relatively new and rapidly emerging avenue with the promise to expand the target space in the drug discovery field. From being "disregarded" as an "undruggable" messenger molecule to FDA approval of an RNA-targeting small-molecule drug Risdiplam, a radical change in perspective toward RNA has been observed in the past decade. RNAs serve important regulatory functions beyond canonical protein synthesis, and their dysregulation has been reported in many diseases. A deeper understanding of RNA biology reveals that RNA molecules can adopt a variety of structures, carrying defined binding pockets that can accommodate smallmolecule drugs. Due to its functional diversity and structural complexity, RNA can be perceived as a prospective target for therapeutic intervention. This perspective highlights the proof of concept of RNA−small-molecule interactions, exemplified by targeting of various transcripts with functional modulators. The advent of RNA-oriented knowledge would help expedite drug discovery. ■ SIGNIFICANCE• This Perspective highlights the importance of RNA as a drug target to solve the issues such as lack of therapeutic treatments for several diseases, increasing resistance against conventional drugs, and tackling the undruggability of various protein targets. • In-depth analysis of various aspects, i.e., small-moleculebinding modes, and current trends required to dig deep into this area of drug discovery are discussed. • The research discussed herein would aid in the development of small-molecule therapeutics.

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Drug-Like Small Molecules That Inhibit Expression of the Oncogenic MicroRNA-21

Cited by 9 publications

References 68 publications

RNA‐Selective Small‐Molecule Ligands: Recent Advances in Live‐Cell Imaging and Drug Discovery

RNA‐Selective Small‐Molecule Ligands: Recent Advances in Live‐Cell Imaging and Drug Discovery

Use of steric blocking antisense oligonucleotides for the targeted inhibition of junction containing precursor microRNAs

RNA–Small-Molecule Interaction: Challenging the “Undruggable” Tag

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