Development of Novel Drugs That Target Coactivation Sites of the Androgen Receptor for Treatment of Antiandrogen-Resistant Prostate Cancer

Prostate cancer is the most commonly diagnosed non-skin cancer in American men and one of the leading causes of cancer-related death. If diagnosed early, when still confined to the prostate, it is frequently curable by surgery or radiotherapy. Treatment for locally advanced, recurrent, or metastatic prostate cancer is primarily some form of androgen withdrawal therapy, which is generally designed to block either the production of androgens or their binding to the androgen receptor (AR). Unfortunately, the effectiveness of this type of treatment is usually temporary due to progression of surviving tumor cells to a castration-resistant state. With no curative treatment options for castration-resistant prostate cancer, the median life expectancy is approximately 18 months.

Part of the problem is that all anti-AR agents currently used to treat patients act by direct binding to the AR's hormone binding site and hence are vulnerable to mutations that frequently arise in this region of the molecule. The proposed research aims to address this problem by using computer modeling, biological screening, and structural biology to develop an entirely new class of anti-AR drugs that will target two other distinct regions of the AR (called BF3 and AF2) to inhibit its activity. We anticipate that these new anti-AR drugs will replace or supplement existing anti-AR therapeutics and will provide new options for treating patients with metastatic, castration-resistant prostate cancer.