Patient diversity and developing drug resistance can undermine the efficiency of existing therapies in a long-term pharmacological treatment of diseases, such as cancer and infections.
One of the promising strategies, in this case, is applying multicomponent therapeutics, leading the way to more personalized medicine. Approved drugs appear to be the ideal starting point for the development of novel multidrug treatments enjoying a fast track to new clinical applications.
Indeed, they are already known to be safe, effective and bioavailable. Last, but not least, they usually have well-defined targets and mechanisms of action.
Another important strategy in modern pharmaceutical research is drug repurposing. Drugs which once failed as effective treatments for one disease might well become “blockbuster” cures for another.
With this in mind, a lot of efforts were put into cataloging the existing drugs approved for human use and in veterinary, which eventually amounted to 14.814 items. However, this set is too large to be suitable for systematic studies by academic researchers and even pharmaceutical companies in combinatorial high-throughput screens (HTS). A pairwise combination of all the molecules in this set would generate more than 100.000.000 data points -- an effort beyond reasonable budgets and capacities of screening facilities.
A New Tool For Drug Repurposing And Multidrug Studies
To solve the above obstacle and provide the drug discovery community with a more suitable and representative tool for systematic study of drug combinations and drug repurposing ideas, CeMM PI Stefan Kubicek and his colleagues created a collection of 308 compounds effectively representing the diversity of structures and molecular targets of all FDA-approved chemical entities -- CeMM Library of Unique Drugs, CLOUD (download zip, 8.25MB).
To create CLOUD scientists, first, determined and extracted 2171 unique active pharmaceutical ingredients from the database of approved drugs, discarding all products with identical compounds. Second, they removed large macromolecules like antibodies as well as salt fragments. Next, they discarded all molecules with mechanisms of biological activity other than protein-ligand interactions. Compounds not used to treat diseases or found only in topical products were removed as well to finally yield a set of 954 systemically active small molecules -- STEAM collection.
At this stage, Kubicek’s group got to “grinding” the remaining set of molecules with the goal of creating a comprehensive collection of compounds that fit on a standard 384-well screening plate.
Researchers appended biological activities to all drugs with known molecular targets and grouped them into 176 classes of similar structure and activity. Sophisticated clustering algorithm allowed to extract 239 representative drugs out of the classes of compounds. Finally, combining the obtained selection with 34 drugs having unknown targets and 35 active forms of prodrugs (that otherwise need to be metabolized to become active) amounted in 308 compounds to become CLOUD -- the world’s first library representing all FDA-approved chemical entities including the active form of prodrugs.
The potential of the CLOUD was already proved on a big scale with CeMM´s highly automated chemical screening platform by identifying a novel synergistic effect of two drugs (flutamide and phenprocoumon (PPC)) on prostate cancer cells. The results of Kubicek´s team with Marco Licciardello as the first author were published recently in Nature Chemical Biology.
"The combination induced massive cell death in prostate cancer cells. We then went back to the entire approved drug list, and indeed, we could show that all drugs from the clusters that flutamide and phenprocoumon represent synergize. Thereby we validated the reductionist concept underlying the CLOUD library," Stefan Kubicek explains.
Together with scientists from the Medical University of Vienna, the Uppsala University, Enamine Ltd, and the Max Planck Institute for Informatics in Saarbrücken, Kubicek’s team proved that the CLOUD is the ideal tool for developing screening assays, discovering new applications for approved active ingredients, and finding new drug combinations.
"In view of these successes, I would predict that this set of compounds will become the world standard for all screening campaigns", Stefan Kubicek emphasizes.