Format

Send to

Choose Destination
Cell Chem Biol. 2018 Sep 20;25(9):1086-1094.e7. doi: 10.1016/j.chembiol.2018.05.015. Epub 2018 Jun 28.

Approved Anti-cancer Drugs Target Oncogenic Non-coding RNAs.

Author information

1
Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
2
California Institute for Biomedical Research (CALIBR), 11119 North Torrey Pines Road, Suite 100, La Jolla, CA 92037, USA.
3
Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA. Electronic address: disney@scripps.edu.

Abstract

Potential RNA drug targets for small molecules are found throughout the human transcriptome, yet small molecules known to elicit a pharmacological response by directly targeting RNA are limited to antibacterials. Herein, we describe AbsorbArray, a small molecule microarray-based approach that allows for unmodified compounds, including FDA-approved drugs, to be probed for binding to RNA motif libraries in a massively parallel format. Several drug classes bind RNA including kinase and topoisomerase inhibitors. The latter avidly bound the motif found in the Dicer site of oncogenic microRNA (miR)-21 and inhibited its processing both in vitro and in cells. The most potent compound de-repressed a downstream protein target and inhibited a miR-21-mediated invasive phenotype. The compound's activity was ablated upon overexpression of pre-miR-21. Target validation via chemical crosslinking and isolation by pull-down showed direct engagement of pre-miR-21 by the small molecule in cells, demonstrating that RNAs should indeed be considered druggable.

KEYWORDS:

RNA; cancer; chemical biology; non-coding RNAs; nucleic acids; rational design; small molecules

PMID:
30251629
PMCID:
PMC6334646
[Available on 2019-09-20]
DOI:
10.1016/j.chembiol.2018.05.015
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center