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- Title
Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA‐Binding Scaffold.
- Authors
Donlic, Anita; Morgan, Brittany S.; Xu, Jason L.; Liu, Anqi; Roble, Jr., Carlos; Hargrove, Amanda E.
- Abstract
Abstract: Structural studies of the 3′‐end of the oncogenic long non‐coding RNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) confirmed a unique triple‐helix structure. This structure enables accumulation of the transcript, and high levels of MALAT1 are found in several cancers. Here, we synthesize a small molecule library based on an RNA‐binding scaffold, diphenylfuran (DPF), screen it against a variety of nucleic acid constructs, and demonstrate for the first time that the MALAT1 triple helix can be selectively targeted with small molecules. Computational analysis revealed a trend between subunit positioning and composition on DPF shape and intramolecular interactions, which in turn generally correlated with selectivity and binding strengths. This work thus provides design strategies toward chemical probe development for the MALAT1 triple helix and suggests that comprehensive analyses of RNA‐focused libraries can generate insights into selective RNA recognition.
- Subjects
SMALL molecules; LIGANDS (Chemistry); RNA-binding proteins; MOLECULAR structure; METASTASIS; LUNG cancer
- Publication
Angewandte Chemie, 2018, Vol 130, Issue 40, p13426
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201808823