A New Class of Drugs to Treat Breast Cancer

Institution: University of California, San Francisco
Investigator(s): Thomas Robertson, Ph.D. -
Award Cycle: 2000 (Cycle VI) Grant #: 6FB-0089 Award: $33,694
Award Type: Postdoctoral Fellowship
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2000)
Selective estrogen receptor modulators (SERMs) are a class of drugs currently in clinical use to treat hormone-responsive breast cancer, postmenopausal osteoporosis and cardiovascular disease. Tamoxifen is a SERM commonly used to treat breast cancer. While tamoxifen has excellent properties in prolonging the lives of women with breast cancer without many undesirable side effects, some people have breast cancer cells that become resistant to tamoxifen treatment. A small increase in the incidence of endometrial cancer has also been observed in women taking tamoxifen, so there is clearly a need to develop new drugs for treating people with breast cancer. Over the past three years the way that tamoxifen prevents the growth of breast cancer cells has been explained at the molecular level. In a normal cell, when the hormone 17b -estradiol comes into contact with a protein called the estrogen receptor (ER) it binds tightly to the protein. The resulting association of hormone and protein is called a complex. The 17b -estradiol: ER complex is a component of a bigger complex that must form as part of a process leading to cell division. Hence, the complex is necessary for cell growth to occur and blocking the formation of this complex inhibits cell growth. By adhering to the estrogen receptor at the same location that the 17 b -estradiol normally binds, metabolites of tamoxifen prevent 17 b -estradiol from stimulating the growth of breast cancer cells.

In addition to providing an explanation of the way that tamoxifen works at the molecular level researchers have located the part of the estrogen receptor that adheres to a protein known as a coactivator protein. Binding between co-activator protein and the ER: 17b -estradiol complex is also an essential step in a process leading to cell division. Hence, a molecule which prevented formation of the co-activator protein: ER: 17b -estradiol complex in breast cancer cells would also block cell growth. We have used computer models of binding between the ER and co-activator protein to design organic molecules that may bind to the ER at the same position as the co-activator protein. We want to prepare a group of chemicals with closely related structures and compare how efficiently each chemical binds to the estrogen receptor. Our goal is to identify molecules that inhibit formation of the co-activator protein: ER complex under the conditions found in breast cancer cells.

If we discover compounds which inhibit complex formation we will synthesize more structurally related compounds with the goal of identifying the best inhibitors of binding between co-activator protein and ER. Such inhibitors could be tested as inhibitors of growth in cultured cancer cells. It would aid in our understanding of the functions of co-activator proteins in cell growth and might ultimately lead to the development of new drugs to treat breast cancer in humans.


Final Report (2001)
Tamoxifen is a leading drug for the treatment of breast cancer. The way that tamoxifen inhibits the progression of breast cancer is well characterized and relies on the binding of tamoxifen to a protein called the estrogen receptor (ER). Our goal is to identify a new class of compounds that inhibit breast cancer growth in a complementary but distinctly different way to tamoxifen. We are attempting to design and identify chemicals that bind to a different part of the ER and which like tamoxifen block formation of the ER: co activator protein complex. Such compounds could overcome the limitations of tamoxifen treatment such as drug resistance and side effects. We have established a high throughput method for identifying potential drugs and we have used computer modeling to identify a group of structurally related chemicals that may inhibit breast cancer growth. As this group of chemicals shares the same structural scaffold we have attempted to make the core scaffold by chemical synthesis. We have tried four different methods of chemical synthesis until we were able to confirm that the target scaffold was forming. However, the target compound only formed in small amounts as part of a complex mixture. Hence, we have now designed a fifth method of synthesis that will reduce or eliminate the formation of by products other than the desired compound.

When an efficient method to make the core scaffold has been identified the next part of the project will involve the synthesis of a series of structurally related compounds. By synthesizing and testing a large series of compounds we hope to identify the features of the best compounds and incorporate these features into a second generation of potential drugs.