Treatment of Castration-Resistant Prostate Cancer Using Agents That Promote Androgen Receptor Degradation

Prostate cancer is the second most common cancer in men in the United States with approximately 161,360 new diagnoses each year. Many patients undergo surgery, chemotherapy, and/or radiation followed by androgen-deprivation therapy (ADT). ADT unfortunately is only a palliative measure, and eventually, these patients develop a fatal form of prostate cancer called castrationresistant prostate cancer (CRPC). The drugs currently available to treat CRPC extend patient lifetimes by only a few months. The molecular mechanisms underlying CRPC occurrence remain unclear, but one hallmark involves increased levels of androgen receptors (AR). I seek to develop new agents for treating CRPC. These new agents will utilize a “drug construct” that takes advantage of the body’s proteindegrading machinery to decrease AR levels. In promising preliminary results, I developed a biologically active surrogate for the male hormone, 5a-dihydrotestosterone (DHT). This DHT surrogate, called “DHT-s” translocated across the cell and nuclear membranes, bound the AR and triggered transcription. Thus, DHT-s behaved identically to the natural DHT hormone. It is my hypothesis that similar analogs of DHT-s are ideal candidates for the development of “proteolysis targeting chimera agents” (PROTACs) that will bind to the androgen receptor and attract E3 ligase enzymes that will ubiquitinate the AR. Once modified, the ubiquitinated AR will undergo proteasomal degradation. In Specific Aim 1, I will synthesize DHT-s surrogates conjugated through linkers to three different ligands that will attract different E3 ligases. I will explore linkers of various lengths and hydrophobic/hydrophilic character for connecting DHT-s to these three ligands. In Specific Aim 2, I will evaluate the levels of ubiquitination and degradation of AR receptor induced by these DHT-based PROTACs in androgen-sensitive LAPC-4, LNCaP, HeLa and 22Rv1 cell lines. The ultimate objective of proposed studies is the development of DHT-based PROTACs as potential drugs for treating CRPC. The short-term objectives of the proposed studies are the synthesis of biologically active PROTACs and demonstration that they promote the degradation of AR receptors via ubiquitin-proteasome pathway.