Academic Commons

Articles

Systematic discovery of multicomponent therapeutics

Borisy, Alexis; Elliott, Peter; Hurst, Nicole; Lee, Margaret; Lehar, Joseph; Price, E. Roydon; Serbedzija, George; Zimmerman, Grant; Foley, Michael; Stockwell, Brent R.; Keith, Curtis

Multicomponent therapies, originating through deliberate mixing of drugs in a clinical setting, through happenstance, and through rational design, have a successful history in a number of areas of medicine, including cancer, infectious diseases, and CNS disorders. We have developed a high-throughput screening method for identifying effective combinations of therapeutic compounds. We report here that systematic screening of combinations of small molecules reveals unexpected interactions between compounds, presumably due to interactions between the pathways on which they act. Through systematic screening of ≈120,000 different two-component combinations of reference-listed drugs, we identified potential multicomponent therapeutics, including (i) fungistatic and analgesic agents that together generate fungicidal activity in drug-resistant Candida albicans, yet do not significantly affect human cells, (ii) glucocorticoid and antiplatelet agents that together suppress the production of tumor necrosis factor-α in human primary peripheral blood mononu-clear cells, and (iii) antipsychotic and antiprotozoal agents that do not exhibit significant antitumor activity alone, yet together prevent the growth of tumors in mice. Systematic combination screening may ultimately be useful for exploring the connectivity of biological pathways and, when performed with reference-listed drugs, may result in the discovery of new combination drug regimens.

Files

  • thumnail for PNAS-2003-Borisy-7977-82.pdf PNAS-2003-Borisy-7977-82.pdf application/pdf 634 KB Download File

Also Published In

Title
Proceedings of the National Academy of Sciences
DOI
https://doi.org/10.1073/pnas.1337088100

More About This Work

Academic Units
Biological Sciences
Publisher
National Academy of Sciences
Published Here
March 5, 2015
Academic Commons provides global access to research and scholarship produced at Columbia University, Barnard College, Teachers College, Union Theological Seminary and Jewish Theological Seminary. Academic Commons is managed by the Columbia University Libraries.