When two drugs are better than one

Drug combinations often have deleterious effects, but a new study reports a method to identify drugs that play nice with each other.

Stefan Kubicek of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and coworkers compiled a compound library to search for drugs that work better together than alone, and they used it to identify a combo that fights drug-resistant cancer (Nat. Chem. Biol. 2017, DOI: 10.1038/nchembio.2382).

The list of more than 30,000 Food & Drug Administration-approved drug products is too large to screen efficiently for favorable combinations. Kubicek and coworkers therefore narrowed down the list to a more easily screenable collection.

They eliminated redundant drug products with identical active ingredients, removed biologicals, and made other selections to reduce the list to 954 systemically active small molecules. They grouped these compounds into classes based on their structures and known activities and then used software to help them select representative agents. The team used those agents and others to create a list of 308 compounds, which they call the CeMM Library of Unique Drugs, or CLOUD.

Screening the CLOUD against cancer cells revealed that the prostate cancer drug flutamide and the antithrombotic agent phenprocoumon work synergistically to kill an otherwise drug-resistant form of prostate cancer. Combinations of non-CLOUD drugs in the same classes as flutamide and phenprocoumon also fight the drug-resistant cancer, helping confirm that the CLOUD compounds successfully represent their classes and that the team’s reductionist concept is valid.

“We believe that the CLOUD is the ideal set of compounds to develop all screening assays and to discover new applications for approved active ingredients,” Kubicek says.