TCD researchers chart chemical space in the search for new breast cancer treatments

Estrogen and the estrogen receptor (ER)

“Estrogen works by locking into the ER, causing a change to the shape of the receptor,” explains Dr Meegan. “This structural change enables the estrogen-receptor complex to bind to coactivator proteins and initiate a cascade of downstream effects resulting in cell proliferation.”

Estrogen promotes cell proliferation in the breast and uterus but in breast cells with DNA mutations this process can increase the risk of developing breast cancer. This increased risk was already shown in studies involving the administration of estrogen to reduce cholesterol and maintain bone density in hormone replacement therapy (HRT).

Tamoxifen and Raloxifene

Two of the current Selective Estrogen Receptor Modulator (SERM) drugs, Tamoxifen and Raloxifene, are antiestrogens and are used for treating breast cancer and osteoporosis respectively.

Tamoxifen mimics estrogen by preventing its binding to estrogen receptors in breast cells, but it can activate estrogen 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 antiestrogen molecules that have improved specificity and toxicology profiles. We are working to identify molecules that are selective at the estrogen receptors in breast cells but which don't have a proliferative effect in other tissues,” continues Dr Meegan.

Discovering new leads using structure-based drug design

Dr Meegan's group takes a practical approach to discovering potential leads for drugs. The estrogen receptor holds the key because its crystal structure and how it binds to antiestrogens 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,” continues Dr Meegan. “As part of his PhD thesis Dr Andrew Knox devised a scoring system to rate molecular fit in the estrogen receptor so we can 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 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 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 optimize the selective binding properties of these antiestrogenic compounds and to elucidate the mechanism of antihormonal resistance,” concludes Dr Meegan.