Small Molecules Block Activity Of MicroRNA Transcription Factors

Researchers have developed a computational method that identifies small molecules that block the function of microRNAs (miRNAs), which are important cellular targets for cancer and other diseases (Nat. Chem. Biol. 2014, DOI: 10.1038/nchembio.1452). One of the agents has a selective type of anticancer activity, suggesting that a drug based on it might have fewer side effects than conventional cancer chemotherapies.

miRNAs are three-dimensionally folded small RNAs that don’t code for proteins but instead regulate gene transcription. They are overexpressed in various diseases, such as cancer, and they modulate key steps in immune reactions.

Except for antibiotics that target RNA in bacterial ribosomes, few small molecules have been developed to modulate RNA function, and miRNAs in particular haven’t been viable drug targets before now. The ability of the new technique to identify small molecules that block miRNA activity could “offer a new set of drugs,” comments Nobel Prize-winning molecular biologist and biochemist Phillip A. Sharp of MIT.

Matthew D. Disney of Scripps Florida and coworkers developed the new approach and used it to identify about two dozen small molecules that interact with sites in miRNAs. Their best drug candidate, a benzimidazole, disables the function of miRNA-96, a cancer-associated miRNA.

Its activity is similar to that of previously developed miRNA-96-inhibiting antagomirs, which are oligo­nucleotides that block the activity of miRNAs by binding to them sequence specifically. But antagomirs don’t enter cells easily and tend to degrade quickly in the body, whereas small molecules such as benzimidazoles are cell permeable and tend to persist longer.

Also unlike antagomirs, the benzimidazole binds to a folded structural motif in a precursor of miRNA-96, not to its sequence per se. The small molecule blocks miRNA-96’s normal function—inhibition of the apo­ptosis-inducing protein FOXO1 in cancer cells. The benzimidazole thus causes cancer cells to die by apoptosis. Cells without FOXO1 protein are unaffected by the compound, suggesting that a drug similar to the benzimidazole might have minimal side effects.

To find the anti-miRNA small molecules, Disney and coworkers used a computational technique named Inforna to predict miRNA secondary structure from sequence and then used a database of small-molecule/RNA interactions to identify cell-permeable compounds that target such structures. The approach’s ability to identify small-molecule drug leads from miRNA sequence is “something many doubted could be done,” Disney says.

“This is a breakthrough in selectively targeting a central class of cellular regulators,” comments RNA-folding bioinformatician Alain Laederach of the University of North Carolina, Chapel Hill. “This type of chemistry opens a whole new world of potential therapeutic targets.”