Defining the RNA Internal Loops Preferred by Benzimidazole Derivatives via 2D Combinatorial Screening and Computational Analysis

Velagapudi, Sai Pradeep; Seedhouse, Steven J.; French, Jarrod B.; Disney, Matthew D.

doi:10.1021/ja200212b

Cited by 46 publications

(94 citation statements)

References 40 publications

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“…Although 3 does not bind to the DNA hairpin (K d > 50,000 nM), 2 binds to this DNA with a K d of 200 nM. Thus, appendage of 2 to 1, a molecule that does not bind DNA because it has bulky t-butyl groups (12,27), ablates the binding of 3 to DNA. Taken together, control of target binding in multivalent ligands depends on the identity of the modules individually and collectively and the distance between them, which has been previously observed (20,28).…”

Section: Resultsmentioning

confidence: 99%

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Design of a small molecule against an oncogenic noncoding RNA

Velagapudi

Cameron

Haga

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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173

187

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The design of precision, preclinical therapeutics from sequence is difficult, but advances in this area, particularly those focused on rational design, could quickly transform the sequence of diseasecausing gene products into lead modalities. Herein, we describe the use of Inforna, a computational approach that enables the rational design of small molecules targeting RNA to quickly provide a potent modulator of oncogenic microRNA-96 (miR-96). We mined the secondary structure of primary microRNA-96 (pri-miR-96) hairpin precursor against a database of RNA motif-small molecule interactions, which identified modules that bound RNA motifs nearby and in the Drosha processing site. Precise linking of these modules together provided Targaprimir-96 (3), which selectively modulates miR-96 production in cancer cells and triggers apoptosis. Importantly, the compound is ineffective on healthy breast cells, and exogenous overexpression of pri-miR-96 reduced compound potency in breast cancer cells. Chemical Cross-Linking and Isolation by Pull-Down (Chem-CLIP), a small-molecule RNA target validation approach, shows that 3 directly engages pri-miR-96 in breast cancer cells. In vivo, 3 has a favorable pharmacokinetic profile and decreases tumor burden in a mouse model of triple-negative breast cancer. Thus, rational design can quickly produce precision, in vivo bioactive lead small molecules against hard-to-treat cancers by targeting oncogenic noncoding RNAs, advancing a disease-to-gene-todrug paradigm.RNA | noncoding RNA | drug design | chemistry | nucleic acids

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Section: Resultsmentioning

confidence: 99%

“…The database is comprised of privileged interactions identified by a library vs. library screen named 2D combinatorial screening (2DCS) (11,12). In 2DCS, a library of array-immobilized small molecules is probed for binding to a library of small RNA motifs that are likely to be present in biological RNAs (11,12).…”

mentioning

confidence: 99%

Design of a small molecule against an oncogenic noncoding RNA

Velagapudi

Cameron

Haga

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

173

187

View full text Add to dashboard Cite

show abstract

“…The authors applied a particularly clever screening methodology called 2D combinatorial screening (2DCS) [65][66][67]. In 2DCS, a small-molecules library is conjugated onto an agarose microarray surface.…”

Section: Focused Screening Approachmentioning

confidence: 99%

Small-Molecule Approaches Toward the Targeting of Oncogenic Mirnas: Roadmap for the Discovery of Rna Modulators

2016

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miRNAs are a recently discovered class of small noncoding RNAs implicated in the regulation of gene expression. The deregulation of miRNAs levels has been linked to the development of various cancers where oncogenic miRNAs are overexpressed and tumor suppressor miRNAs are underexpressed. Here we report the three main strategies developed in order to discover small-molecule drugs able to selectively interfere with oncogenic miRNAs: the high throughput screening of large libraries of compounds, the focused screening of small libraries of molecules that are known to be able to interact with RNA thus being supposed modulators of miRNAs pathway and the design of small molecules based on the secondary structure of targeted RNA and/or three-dimensional structure of enzymes involved in miRNAs pathway.

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“…Velagapudi et al 123 reported a new method called Inforna for sequence-based design of SMIR to target pre-miRs. Inforna integrated a selection-based strategy (Two-Dimensional Combinatorial Screening; 2DCS), 124 a statistical approach (Structure-Activity Relationship through Sequencing; StARTS), 125,126 and the structural information about the RNA target of interest that identified RNA motifs that positively and negatively contributed to binding. After screening and optimization, they selected three compounds for miR-96 precursor, miR-210 precursor, and miR-182 precursor, respectively.…”

Section: Small Molecule Mirna Therapeutic Agentsmentioning

confidence: 99%

Small molecules targeting microRNA for cancer therapy: Promises and obstacles

Wen

Danquah

Chaudhary

et al. 2015

Journal of Controlled Release

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Aberrant expression of miRNAs is critically implicated in cancer initiation and progression. Therapeutic approaches focused on regulating miRNAs are therefore a promising approach for treating cancer. Antisense oligonucleotides, miRNA sponges, and CRISPR/Cas9 genome editing systems are being investigated as tools for regulating miRNAs. Despite the accruing insights in the use of these tools, delivery concerns have mitigated clinical application of such systems. In contrast, little attention has been given to the potential of small molecules to modulate miRNA expression for cancer therapy. In these years, many researches proved that small molecules targeting cancer-related miRNAs might have greater potential for cancer treatment. Small molecules targeting cancer related miRNAs showed significantly promising results in different cancer models. However, there are still several obstacles hindering the progress and clinical application in this area. This review discusses the development, mechanisms and application of small molecules for modulating oncogenic miRNAs (oncomiRs). Attention has also been given to screening technologies and perspectives aimed to facilitate clinical translation for small molecule-based miRNA therapeutics.

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Defining the RNA Internal Loops Preferred by Benzimidazole Derivatives via 2D Combinatorial Screening and Computational Analysis

Cited by 46 publications

References 40 publications

Design of a small molecule against an oncogenic noncoding RNA

Design of a small molecule against an oncogenic noncoding RNA

Small-Molecule Approaches Toward the Targeting of Oncogenic Mirnas: Roadmap for the Discovery of Rna Modulators

Small molecules targeting microRNA for cancer therapy: Promises and obstacles

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