The Natural Product Butylcycloheptyl Prodiginine Binds Pre-miR-21, Inhibits Dicer-Mediated Processing of Pre-miR-21, and Blocks Cellular Proliferation

Author:

Matarlo, Joe S

Haugh Krumpe,Lauren

Heinz,Will

Oh, Daniel

Shenoy, Shilpa R

Thomas,Cheryl

Goncharova,Katya

Lockett,Stephen

O'Keefe,Barry
Author Address

Molecular Targets Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA., Molecular Targets Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Molecular Targets Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; Biomedical Informatics and Data Science Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Molecular Targets Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. Electronic address: okeefeba@mail.nih.gov.,

Abstract:

Identification of RNA-interacting pharmacophores could provide chemical probes and, potentially, small molecules for RNA-based therapeutics. Using a high-throughput differential scanning fluorimetry assay, we identified small-molecule natural products with the capacity to bind the discrete stem-looped structure of pre-miR-21. The most potent compound identified was a prodiginine-type compound, butylcycloheptyl prodiginine (bPGN), with the ability to inhibit Dicer-mediated processing of pre-miR-21 in vitro and in cells. Time-dependent RT-qPCR, western blot, and transcriptomic analyses showed modulation of miR-21 expression and its target genes such as PDCD4 and PTEN upon treatment with bPGN, supporting on-target inhibition. Consequently, inhibition of cellular proliferation in HCT-116 colorectal cancer cells was also observed when treated with bPGN. The discovery that bPGN can bind and modulate the expression of regulatory RNAs such as miR-21 helps set the stage for further development of this class of natural product as a molecular probe or therapeutic agent against miRNA-dependent diseases. Published by Elsevier Ltd.

See More

Author Address