NCI Cancer Bulletin: A Trusted Source for Cancer Research News
NCI Cancer Bulletin: A Trusted Source for Cancer Research News
August 19, 2008 • Volume 5 / Number 17 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Treatment Arsenal Expands with Small Chemicals

The proprietary, one-at-a-time approach to developing safe agents for specific diseases has produced hundreds of drugs in the last 50 years. But those numbers are meager compared to what the future holds.

The laboratory of Dr. Stuart Schreiber, the Harvard-trained organic chemist and founding professor at the Broad Institute of Harvard and MIT, has created a powerful, revolutionary method of synthetic chemistry to actually reach the goal of targeting cancer dependencies - diversity oriented synthesis. "It's likely that many of the proteome's 100,000 proteins have multifunctional roles in cancer, and it follows that molecules that control them will yield a therapeutic benefit," he says.

In 2002, the NCI Office of Cancer Genomics selected Dr. Schreiber's lab as a center in the Initiative for Chemical Genetics (ICG). As the number of useful small molecules they could develop became apparent, a more comprehensive strategy began to coalesce into a new field altogether, known as chemical biology. The ICG essentially provides a national laboratory for high-throughput, small-molecule screening, and has generated and analyzed data for more than 100 different research groups.

Another open-source, data-sharing model Dr. Schreiber has developed is ChemBank, a public, Web-based informatics environment to facilitate chemical genetics.

Chembank provides life scientists access to tools that are associated with private sector industry, and to data from hundreds of biomedically relevant assays that link the states of healthy and diseased cells to more than 700,000 small molecules. This kind of community resource, Dr. Schreiber believes, "enables the drug-hunting community to become more than the sum of its parts."  

CMap Extends Drug Use

Drs. Todd Golub, Justin Lamb, and colleagues at the Broad Institute have created a public database of gene-expression profiles and Web-based data-mining tools they call the Connectivity Map (CMap), which allows researchers to uncover functional connections between diseases, gene function, and drug actions.

Using 7,056 genome-wide expression microarrays, CMap provides data for how 1,309 small molecules - including virtually all of the off-patent drugs approved by the Food and Drug Administration (FDA) - have modified mRNA expression in a collection of different cultured human cell lines.

This means that users can query the database with a gene-expression signature of a newly developed small molecule; disease tissue; or a genetic variant, such as a knockout; and immediately identify functionally related chemicals. The result might point to a pathway or specific compounds that could modulate that biological state, possibly even FDA-approved drugs that could be tested as a therapy.

Dr. Lamb and his colleagues have demonstrated some discoveries with CMap, but he is much prouder of the small but growing number of completely independent users who have made crucial connections. Even pharmaceutical companies that traditionally operate with strict confidentiality are enthusiastic about platforms like CMap for sharing basic cell biology data, says Dr. Lamb.