Characterization of a novel class of non-competitive androgen receptor antagonists
Abstract
Castration-resistant prostate cancer (CRPC) is currently incurable and makes prostate cancer the second most common cause of cancer death in U.S. males. Second-generation androgen receptor (AR) targeting agents such as enzalutamide and abiraterone can prolong CRPC patient life for several months on average. CRPC develops resistance to these AR targeting agents, and AR reactivation is the major mechanism leading to the resistance. Thus, novel strategies to suppress reactivated AR in CRPC are urgently needed. One strategy to suppress reactivated AR is to reduce AR level in the nuclei of CRPC cells, since a prerequisite for AR to function is its presence in the nucleus where it activates the expression of its target genes. We have developed a high-throughput screen to discover small molecules that can inhibit AR levels in the nuclei in CRPC cells. A screen of a library of ~220,000 small molecules identified two compounds that can reduce AR levels in the nuclei of CRPC cells. One of them can also inhibit ARv7, an AR splice variant that is insensitive to enzalutamide or other FDA-approved AR targeting agents. This compound and its analogs are well tolerated and can be used via oral gavage in animals in preclinical studies. Preliminary studies also showed that this AR antagonist and its analogs are effective in the inhibition of CRPC, including enzalutamide-resistant CRPC. A major goal of our research is to develop more potent analogs of this novel class AR antagonists with improved physicochemical properties and bioavailability that can be used as a single agent or in combination with enzalutamide for the treatment of CRPC. However, it is not yet clear how this class of novel AR antagonists binds to AR, which limits the discovery of more potent analogues. The proposed structural and functional analysis of this novel class of AR antagonists will greatly facilitate the rational development of more potent analogues that may lead to a new therapy for CRPC. This multidisciplinary project will (1) determine how this class of novel non-competitive AR antagonists bind to AR using structural and other analytical techniques, (2) design, synthesize and analyze more effective drug-like analogues, and (3) determine the efficacy of promising new analogs, and their synergy with enzalutamide, to inhibit CRPC tumor growth. The success of this project will provide a strong foundation and guidance for future clinical studies of this class of novel AR antagonists in patients with CRPC, as a single agent or in combination with enzalutamide. Thus, the proposed project will address the following FY22 PCRP Overarching Challenge, Develop treatments that improve outcomes for men with lethal prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310295
Entities
People
- Zhou Wang
Organizations
- United States Army