Issue 5, 2024

Live cell screening to identify RNA-binding small molecule inhibitors of the pre-let-7–Lin28 RNA–protein interaction

Abstract

Dysregulation of the networking of RNA-binding proteins (RBPs) and RNAs drives many human diseases, including cancers, and the targeting of RNA–protein interactions (RPIs) has emerged as an exciting area of RNA-targeted drug discovery. Accordingly, methods that enable the discovery of cell-active small molecule modulators of RPIs are needed to propel this emerging field forward. Herein, we describe the application of live-cell assay technology, RNA interaction with protein-mediated complementation assay (RiPCA), for high-throughput screening to identify small molecule inhibitors of the pre-let-7d–Lin28A RPI. Utilizing a combination of RNA-biased small molecules and virtual screening hits, we discovered an RNA-binding small molecule that can disrupt the pre-let-7–Lin28 interaction demonstrating the potential of RiPCA for advancing RPI-targeted drug discovery.

Graphical abstract: Live cell screening to identify RNA-binding small molecule inhibitors of the pre-let-7–Lin28 RNA–protein interaction

Supplementary files

Article information

Article type
Research Article
Submitted
21 Feb 2024
Accepted
16 Mar 2024
First published
19 Mar 2024
This article is Open Access
Creative Commons BY-NC license

RSC Med. Chem., 2024,15, 1539-1546

Live cell screening to identify RNA-binding small molecule inhibitors of the pre-let-7–Lin28 RNA–protein interaction

S. L. Rosenblum, D. M. Soueid, G. Giambasu, S. Vander Roest, A. Pasternak, E. F. DiMauro, V. Simov and A. L. Garner, RSC Med. Chem., 2024, 15, 1539 DOI: 10.1039/D4MD00123K

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