Various studies have shown that selective molecular recognition of RNA targets by small molecules in cells, although challenging, is indeed possible. One facile strategy to enhance selectivity and potency is binding two or more sites within an RNA simultaneously with a single molecule. To simplify the identification of targets amenable to such a strategy, we informatically mined all human microRNA (miRNA) precursors to identify those with two proximal noncanonically paired sites. We selected oncogenic microRNA-27a (miR-27a) for further study as a lead molecule binds its Drosha site and a nearby internal loop, affording a homodimer that potently and specifically inhibits miR-27a processing in both breast cancer and prostate cancer cells. This reduction of mature miR-27a ameliorates an oncogenic cellular phenotype with nanomolar activity. Collectively, these studies demonstrate that synergistic bioinformatic and experimental approaches can define targets that may be more amenable to small molecule targeting than others.
Bibliographical noteFunding Information:
We thank J. Childs-Disney for help writing this manuscript. We also thank the agencies that funded this work including the National Institutes of Health (R01 CA249180 to M.D.D), the Myotonic US Fellowship Research Grant (to R.I.B. and S.C.), and the National Ataxia Foundation Fellowship Research Grant (to R.I.B.).
© 2021 American Chemical Society
- Antineoplastic Agents/chemistry
- Breast Neoplasms
- Cell Line, Tumor
- Computational Biology
- Drug Delivery Systems
- MicroRNAs/antagonists & inhibitors
- Prostatic Neoplasms