Faculty, Staff and Student Publications
Publication Date
2-17-2023
Journal
ACS Chemical Biology
Abstract
We report the discovery of drug-like small molecules that bind specifically to the precursor of the oncogenic and pro-inflammatory microRNA-21 with mid-nanomolar affinity. The small molecules target a local structure at the Dicer cleavage site and induce distinctive structural changes in the RNA, which correlate with specific inhibition of miRNA processing. Structurally conservative single nucleotide substitutions eliminate the conformational change induced by the small molecules, which is also not observed in other miRNA precursors. The most potent of these compounds reduces cellular proliferation and miR-21 levels in cancer cell lines without inhibiting kinases or classical receptors, while closely related compounds without this specific binding activity are inactive in cells. These molecules are highly ligand-efficient (MW < 330) and display specific biochemical and cellular activity by suppressing the maturation of miR-21, thereby providing an avenue toward therapeutic development in multiple diseases where miR-21 is abnormally expressed.
Keywords
MicroRNAs, Cell Line
DOI
10.1021/acschembio.2c00502
PMID
36727622
PMCID
PMC10593481
PubMedCentral® Posted Date
2-17-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Included in
Bioinformatics Commons, Biology Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Oncology Commons