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Proc Natl Acad Sci U S A. 2016 May 24;113(21):5898-903. doi: 10.1073/pnas.1523975113. Epub 2016 May 11.

Design of a small molecule against an oncogenic noncoding RNA.

Author information

1
Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
2
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458;
3
Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458 disney@scripps.edu.

Abstract

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 disease-causing 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-to-drug paradigm.

KEYWORDS:

RNA; chemistry; drug design; noncoding RNA; nucleic acids

PMID:
27170187
PMCID:
PMC4889373
DOI:
10.1073/pnas.1523975113
[Indexed for MEDLINE]
Free PMC Article

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