Small Molecules Targeting AR in Castration-Resistant Prostate Cancer
Abstract
Castration-resistant prostate cancer (CRPC) is currently incurable and makes prostate cancer the second most common cause of cancer death in US males. Abiraterone and MDV3100 (enzalutamide®) are two Food and Drug Administration-approved drugs that target androgen signaling in CRPC and can prolong patient life for several months on average. Novel androgen receptor (AR) antagonists are urgently needed, since AR becomes reactivated again in prostate tumors resistant to these new drugs. We have developed a high-throughput screen to discover small molecules that can inhibit AR level in the nucleus in CRPC cells, and screened a library of ~220,000 small molecules. We have identified three active compounds that can specifically inhibit nuclear AR in CRPC cells, which is necessary for cell growth. These compounds are different from any of the known AR antagonists. In our ongoing studies, the lead structure was shown to bind to AR directly and inhibit the proliferation of all tested AR-positive, but not AR-negative, prostate cancer cell lines in culture dish. Importantly, this compound also inhibited the growth of 22Rv1 prostate tumor, which is resistant to MDV3100 (enzalutamide). Therefore, this lead compound has the potential to overcome emerging resistance of CRPC to MDV3100. The success of this project will lead to urgently needed new therapeutics for prostate cancer patients who are resistant to abiraterone and/or MDV3100 or have relapsed after their treatment. Our lead compound is well-tolerated in mice, which is consistent with its inhibition of AR-positive but not AR-negative prostate cancer cells. Thus, therapeutics based on our lead compound will likely have low toxicity with few side effects on patients. The synthesis of analogs of the lead compound and analysis of their structure-activity relationship represents an essential step in finding the best possible clinical candidate(s). The success of this project will enable us to attract and establish future collaborations with the pharmaceutical industry for further drug development and Phase I-III clinical trials in the next few years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610659
Entities
People
- Zhou Wang
Organizations
- United States Army
- University of Pittsburgh