Scientists have found a computational method that charts chemical space in the search for new breast cancer treatments. The technique has already resulted in the discovery of compounds that have performed better than current standard antioestrogen drug tamoxifen. Breast cancer is a cancer of breast tissue. Worldwide, it is the most common form of cancer in females but not so much in males, affecting, at some time in their lives, approximately one out of nine to thirteen women who reach age ninety the Western world. It is the second most fatal cancer in women (after lung cancer), and the number of cases has significantly increased since the 1970s, a phenomenon partly blamed on modern lifestyles in the Western world that has been dubbed “the influence of Tokyo Joe,” in some European countries. Dr Mary Meegan from the School of Pharmacy and Pharmaceutical Sciences in Trinity College Dublin took a practical approach to discovering potential leads for drugs. The team discovered that the oestrogen receptor holds the key because its crystal structure and how it binds to antioestrogens is well documented. Using computational methods researchers can screen potential leads by studying their 3D conformations and binding properties. "We group molecules with specific cancer activity together and analyse them in chemical space," said Meegan. "Fellow researcher, Dr Andrew Knox devised a scoring system to rate molecular fit in the oestrogen receptor so as to accurately predict new leads." Dr Knox screened thousands of molecules from drug databases using his own screening methods. He was able to narrow the search by devising a ranked hitlist where molecules with the highest score were identified for further exploration and biochemical testing. "The results so far have been very encouraging in that a number of the compounds identified perform better than tamoxifen as antioestrogens and are showing no adverse effect in uterine cells.” “We are currently working to optimise the selective binding properties of these antiestrogenic compounds and to elucidate the mechanism of antihormonal resistance," added Meegan. Two of the current selective estrogen receptor modulator (SERM) drugs, tamoxifen and Eli Lilly's Evista (raloxifene), are antioestrogens and are used for treating breast cancer and osteoporosis respectively. Tamoxifen mimics oestrogen by preventing its binding to oestrogen receptors in breast cells, but it can activate oestrogen receptors in the uterus and long-term use is associated with a small increase in the risk of uterine cancer. However, it remains one of the endocrine drugs of choice for the treatment of breast cancer. Raloxifene in contrast reduces the risk of endometrial cancer and is currently used to treat osteoporosis. Both drugs have benefits and limitations and a clinical trial called the Study of Tamoxifen and Raloxifene (STAR), due to finish this year, aims to evaluate their ability to prevent breast cancer in women who are at high risk of developing the disease. "There is a requirement for new antioestrogen molecules that have improved specificity and toxicology profiles. We are working to identify molecules that are selective at the oestrogen receptors in breast cells but which don't have a proliferative effect in other tissues," said Dr Meegan. The next step in the drug discovery process was to set up a synthetic programme to explore the structure of the molecules and to design and synthesise analogues for further testing. Dr Meegan's research group is working to develop efficient synthetic routes to the various series of compound structures identified by Dr Knox. They have tested them against osterogen receptor (ER) positive, ER negative and uterine cancer lines to confirm that their action is mediated through the ER. "The results so far have been very encouraging in that a number of the compounds identified perform better than tamoxifen as antiestrogens and are showing no adverse effect in uterine cells.” “We are currently working to optimise the selective binding properties of these antiestrogenic compounds and to elucidate the mechanism of antihormonal resistance," concluded Meegan.