Development of Mechanistically Distinct Androgen Receptor Antagonists and Degraders for the Treatment of Advanced Castration-Resistant Prostate Cancer
Abstract
Androgens like testosterone are sex steroid hormones that function by binding to and activating the androgen receptor (AR). Acting through AR, these hormones are responsible for the secondary sexual characteristics (growth of sex accessory organs, body and facial hair growth, increase in muscle mass) associated with adolescence in males. Importantly, AR is also critical for prostate gland development and is thought to contribute to the progression of prostate cancer. Prostate cancer is the second most common cancer in men, trailing only cancer of the skin. Greater than 28,000 deaths were attributed to this disease in the United States in 2012, accounting for 10% of all cancer deaths in males. In fact, 17% of all American men will eventually develop invasive prostate cancer over their lifetime. Patients with advanced or metastatic prostate cancer typically undergo hormonal therapies designed to block androgen production (LH-RH agonist, Lupron; CYP17 inhibition, Zytiga) as well as block AR activity (antiandrogen, Xtandi). These treatments are not curative as resistance to therapy is common and often fatal. Recent studies show that even in the absence of an androgenic stimulus, the AR remains a key regulator of the transition from hormone-sensitive to hormone-resistant disease, placing this receptor at the epicenter of new therapies designed to treat advanced prostate cancer. In the preliminary studies presented, we detail the development of a completely new approach to antiandrogen discovery, one that simultaneously blocks multiple roads to resistance development. In addition, we describe the functional properties of three mechanistically different classes of compounds that we believe represent a fundamental advance in our ability to pharmacologically manipulate AR. These agents either degrade AR upon binding or trap AR in unproductive sub-cellular fractions, thus abolishing AR signaling in ways that are difficult to overcome for resistance development. Importantly, these molecules have been shown to inhibit the activity of AR in assays where clinically approved antiandrogens (including Xtandi) have no inhibitory activity. These results suggest that antiandrogens that function in mechanistically novel ways, like the ones we are developing, may be beneficial for the treatment of advanced prostate cancer in settings where AR is implicated in tumor growth. The first and second specific aims will address the need to develop pharmaceutically optimized antiandrogens that have increased activity against AR. This will be achieved through medicinal chemistry and the application of our novel screening technologies. The resulting new compounds will then be tested in assays of AR function to ensure that they still behave as antagonists with similar properties to the original compounds. In the final aim, we will test these new antiandrogens in animal models of advanced castration-resistant prostate cancer. As there is currently no treatment for this stage of prostate cancer, the studies described here will be an important first step in determining the feasibility of targeting AR for the treatment of the most advanced forms of this disease. In short, we believe that our new mechanism-based approach towards novel antiandrogen discovery will have a significant impact on the pharmacotherapy of prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510720
Entities
People
- Donald P McDonnell
Organizations
- Duke University
- United States Army