Old Drugs, New Tricks
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Recently, many initiatives from national centers, translational units and pharma companies have focused on screening approved pharmaceuticals for new indications: repurposing, rescuing or repositioning drugs. NCATS (National Center for Advancing Translational Sciences) reports that the need for this approach stems from the long approval process and the bulk of data already available on tested compounds. Specifically, drug "rescue" refers to research involving small molecules and biologics whose development was stopped before approved by FDA, whereas "repurposing" or "repositioning" refers to the testing of small molecules and biologics already approved to treat a disease or condition to see if they are safe and effective for treating other diseases. For years, pharmaceutical companies have discovered 'new uses for old drugs' but mostly through serendipity or as a result of report(s) of adverse effects. It is a standard practice to remove compounds (and similar analogs) from pharma screening collections once they are selected as potential therapeutics...so many potential target-drug interactions are unexplored by industry unless reported during clinical trials or post-NDA. Access to this type of information is a potential " therapeutic gold mine" for researchers in academics as many steps in approval process for indications can be shortened without the need to do extensive safety and toxicology studies. The Center for Chemical Genomics (CCG) has several collections to help researchers with this approach to drug and probe discovery. The MicroSource Spectrum 2400 is an expanded collection that includes 1600 compounds with drug approval in US, Europe and/or Japan. The LOPAC collection and Prestwick will also be available soon to screeners to provide additional drugs and templates for repurposing. These new acquisitions supplement the CCG's existing 194K collection comprised of diverse small molecules, fragments, natural product extracts, oncology and focused libraries. All are available on 96-, 384- or 1536-well formats for testing in biochemical or cell-based assays. The CCG has already helped several UM researchers identify drugs for repurposed use. A publication by John Tesmer describes the discovery that Paxil (an antidepressant) inhibits GRK2 and is implicated in myocardial contraction. In a screen for inhibitors of IKKε, amlexanox (used to treat canker sores) was identified as an assay hit and further testing of this drug provided evidence suggesting that inflammation is a crucial link between obesity and insulin resistance. In the Neubig laboratory, cell-based screening revealed that digoxin enhances RGS2/RGS4 expression and function, which could explain that drug's protective mechanism against high blood pressure and heart failure.
These are three examples of potential repositioning from screens developed in the CCG. This fall, the CCG (in collaboration with CDNM) has invited a number of drug discovery speakers including Michael Pollastri from Northeastern University. He has used repurposing approaches for the treatment of parasitic diseases. His lecture will be October 25 at 9am in Palmer Commons. |
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The Center for Chemical Genomics (CCG) assists researchers in carrying out high-throughput screens of chemical and siRNA libraries to identify new tools for biological research. The CCG also provides access to MScreen, an open-source, high-throughput (HTS) data storage and analysis system.
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