"Breast cancer is the third most frequent cancer in the world (796,000 cases in 1990). The world total in 2010 is expected to be around 1.45 million, an 82% increase over the figure for 1990."

Global Cancer Statistics, D. Max Parkin, MD, Paola Pisani, PhD, J. Ferlay, CA CANCER J CLIN 1999;49:33-64

The need for an improved breast cancer treatment is well established. One out of eight women will develop breast cancer in her lifetime. The National Cancer Institute predicted 45,000 deaths in the United States from breast cancer in 1999. Current therapies include combination chemotherapy, radiation and hormonal therapy. The involvement of estrogens in the development and progression of breast cancer has been known for over 100 years. Interfering with the activity of endogenously produced estrogens can modulate the course of many estrogen-dependent diseases, including breast cancers. One approach has been to interrupt estrogen activity at the receptor level using estrogen antagonists or antiestrogens. We believe there is a significant market opportunity for a competitive orally-available antiestrogen with an improved therapeutic profile.

Our discovery program has generated three novel chemical classes of estrogen receptor modulators. Representatives from two classes were taken forward into synthesis and biological testing. Synthesis was accomplished with good overall yield and routes are easily scalable for production of larger quantities. Preliminary biological findings are encouraging with positive results in three different in vitro assays. Four compounds were tested in breast cancer cell assays and all four inhibited estradiol-stimulated proliferation. Five compounds were tested in an estradiol competitive binding assay and all five demonstrated potent inhibition of estradiol binding to both the ERa and ERb subtypes. Two compounds were tested in a gene transfection assay and both inhibited estrogen-stimulated transcription through ERa and ERb subtypes. No significant estrogenicity or cytotoxicity was observed during in vitro testing.

Additional biological testing is required to fully characterize this portfolio of molecules. Based on the in vitro results, in vivo testing will be pursued in a rat uterotrophic model to ensure lack of stimulation on uterine tissues. Evaluation of these candidates in breast cancer animal models will further demonstrate efficacy against this disease. Patent applications have been prepared and will be filed shortly.

The results obtained thus far are a strong indication that these candidates can be developed into valuable therapeutics for the treatment of breast cancer and also validate our ability to design novel compounds with specified activities.