ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 May 02; Vol. 15 (6), pp. 814-821. Date of Electronic Publication: 2024 May 02 (Print Publication: 2024).

Publisher: American Chemical Society Country of Publication: United States NLM ID: 101521073 Publication Model: eCollection Cited Medium: Print ISSN: 1948-5875 (Print) Linking ISSN: 19485875 NLM ISO Abbreviation: ACS Med Chem Lett Subsets: PubMed not MEDLINE

Competing Interests: The authors declare no competing financial interest.
RNAs are increasingly considered valuable therapeutic targets, and the development of methods to identify and validate both RNA targets and ligands is more important than ever. Here, we utilized a bioinformatic approach to identify a hairpin-containing RNA G-quadruplex (rG4) in the 5' untranslated region (5' UTR) of DHX15 mRNA. By using a novel competitive small molecule microarray (SMM) approach, we identified a compound that specifically binds to the DHX15 rG4 ( KD = 12.6 ± 1.0 μM). This rG4 directly impacts translation of a DHX15 reporter mRNA in vitro , and binding of our compound ( F1 ) to the structure inhibits translation up to 57% (IC 50 = 22.9 ± 3.8 μM). This methodology allowed us to identify and target the mRNA of a cancer-relevant helicase with no known inhibitors. Our target identification method and the novelty of our screening approach make our work informative for future development of novel small molecule cancer therapeutics for RNA targets.
(Not subject to U.S. Copyright. Published 2024 by American Chemical Society.)