4.5 Article

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

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CELL CHEMICAL BIOLOGY
卷 26, 期 8, 页码 1133-+

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CELL PRESS
DOI: 10.1016/j.chembiol.2019.04.011

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资金

  1. National Cancer Institute, National Institutes of Health [HHSN26120080001E]
  2. Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research
  3. National Cancer Institute Director's Innovation Award
  4. NATIONAL CANCER INSTITUTE [ZIABC011471] Funding Source: NIH RePORTER

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Identification of RNA-interacting pharmacophores could provide chemical probes and, potentially, small molecules for RNA-based therapeutics. Using a highthroughput 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.

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