Issue 43, 2016

Identification of small molecule inhibitors of the Lin28-mediated blockage of pre-let-7g processing

Abstract

The protein Lin28 and microRNA let-7 play critical roles in mammalian development and human disease. Lin28 inhibits let-7 biogenesis through direct interaction with let-7 precursors (pre-let-7). Accumulating evidence in vitro and in vivo suggests this interaction plays a dominant role in embryonic stem cell self-renewal and tumorigenesis. Thus the Lin28–let-7 interaction might be an attractive drug target, if not for the well-known difficulties in targeting protein–RNA interactions with drugs. The identification and development of suitable probe molecules to further elucidate therapeutic potential, as well as mechanistic details of this pathway will be valuable. We report the development and application of a biophysical high-throughput screening assay for the identification of small molecule inhibitors of the Lin28–pre-let-7 interaction. A library of pharmacologically active small molecules was screened and several small molecule inhibitors were identified and biochemically validated. Of these four validated inhibitors, two compounds successfully restored processing of pre-let-7g in the presence of Lin28, validating the concept. Thus, we have identified examples of small molecule inhibitors of the interaction between Lin28 and pre-let-7. This study provides a proof of concept for small molecule inhibitors that antagonise the effects of Lin28 and enhance processing of let-7 miRNA.

Graphical abstract: Identification of small molecule inhibitors of the Lin28-mediated blockage of pre-let-7g processing

Supplementary files

Article information

Article type
Paper
Submitted
03 Sep 2016
Accepted
04 Oct 2016
First published
04 Oct 2016
This article is Open Access
Creative Commons BY license

Org. Biomol. Chem., 2016,14, 10208-10216

Identification of small molecule inhibitors of the Lin28-mediated blockage of pre-let-7g processing

H. L. Lightfoot, E. A. Miska and S. Balasubramanian, Org. Biomol. Chem., 2016, 14, 10208 DOI: 10.1039/C6OB01945E

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements