New Test Helps Identify Cancer Drug Candidates

By Eric Sauter

Scientists at The Scripps Research Institute's Scripps Florida facilities have developed a novel method to help determine the probable effectiveness of drug candidates for the treatment of estrogen-dependent disorders such as breast cancer and osteoporosis.

These findings could lead to the development of a new generation of optimized selective estrogen receptor modulators (SERMs) with specific binding modes on the target.

The study is being published in the online Early Edition of the journal Proceedings of the National Academy of Sciences (PNAS).

"With new drug candidates, you must make certain that you have the right interaction with the target," said Patrick Griffin, Scripps Research professor and chair of molecular therapeutics and director of the Translational Research Institute at Scripps Florida, "and you need to be able to accurately predict the full range of activity of that potential candidate. Our single biochemical test compares new drug candidates against currently available SERMs, so that you can determine, in rapid fashion, if the new compound is worth pursuing."

Traditional drug discovery programs involve multiple complex assays to determine the tissue selectivity of potent modulators or ligands (molecules that bind to specific sites on a target protein) for estrogen receptors. Unfortunately, translating these extensive, very time consuming laboratory tests into clinically relevant tissue selectivity has been limited, the study said. 

"Our technology at Scripps Florida has enormous potential in the development of new treatments for breast cancer —and for diseases beyond cancer, including cardiovascular disease and osteoporosis," Griffin said. "As a single biochemical assay, this new platform can replace the current load of expensive, multiple cell-based procedures that may take weeks to achieve useful results."

In rapid screening mode, Griffin noted, the new test can review 40 to 50 compounds per week.

"Given the relative slowness of traditional studies, anything that can help rationally filter potential compounds that may be important for women's health is a plus," he said.

An Important Filter

The scientists looked at compounds that affected estrogen receptors, important regulators of the reproductive system that help maintain skeletal and cardiovascular tone. Since estrogen is involved in diseases such as breast cancer and osteoporosis, estrogen receptors are targeted therapeutically for these conditions.

In the study, Scripps Florida scientists used hydrogen/deuterium mass spectrometry to measure the interaction of various ligands with the estrogen receptor. A mass spectrometer determines the mass of a molecule by measuring the mass-to-charge ratio of its ions. Hydrogen/deuterium mass spectrometry is a mass-encoded technique that provides a sensor for the local environment of the ligand binding area in a protein. The results showed the specific regions of the protein that interact with the ligand and the structural changes that result from that interaction. Using well characterized compounds as controls, the new test offers an accurate prediction of how such a new compound will perform in animal models, a critical advantage if you want to optimize a compound for a specific response.

"Using current treatments as model molecules or controls," Griffin said, "our test allows you to filter out those candidates that have different interactions with the target receptor and focus on those that have preferred interactions. The new test is highly sensitive, rapid, and can be done under physiologically relevant conditions. We are able to distinguish between structurally similar compounds, even those with subtle differences, in a meaningful way."

Others authors of the study, Prediction of the Tissue-Specificity of Selective Estrogen Receptor Modulators using a Single Biochemical Method, include Susie Y. Dai, Michael J. Chalmers and John Bruning of The Scripps Research Institute; and Kelli S. Bramlett, Harold E. Osborne, Chahrzad Montrose-Rafizadeh, Robert J. Barr, Yong Wang, Minmin Wang, Thomas P. Burris and Jeffrey A. Dodge of Lilly Research Laboratories.

The study was supported by the State of Florida, Eli Lilly Research Laboratories, and the National Institutes of Health.

Send comments to: mikaono[at]scripps.edu

"The new test is highly sensitive, rapid, and can be done under physiologically relevant conditions," says Scripps Florida investigator Patrick Griffin.