Full Project 3: Novel Bifunctional Anti-Andrgoens for Prostate Cancer

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During the progression of prostatic cancer, malignant cells undergo molecular changes in which AR interacts with partner proteins to generate genomic as well as non-genomic signaling which allows their continuing growth in the presence of low circulating serum T produced by androgen ablation. Thus, these cells are not eliminated by standard androgen ablation (i.e.,LHRH+/-casodex) and their continuous growth eventually kills the patient. Such lethality is highest among our African-American males within the United States. To address this health disparity, developing effective therapy for such androgen ablation resistant patients is the focus of the present application. Our working hypothesis is that why present androoen ablation therapy is of limited efficacy because the conformation of the AR protein when either unoccupied or bound bv low molecular weight partial agonist or antagonist, like Casodex. can be "forced" by the binding of co-activators to displace co-repressors and undergo a change to a full agonist conformation inducing growth stimulation signaling. Therefore, a novel strategy to block such AR growth signaling in androgen ablation failing patients is to develop "bulky bifunctional anti-androgens which bind to the ligand binding domain of AR and structurally lock the AF-2 domain of the AR surface in an antagonist conformation not allowing its AF-2 domain to be "forced" into the agonist state. Therefore Specific Aim 1 is to design and synthesize a series of benzyl or alkyl 11beta and 7alpha side chain-delta9-19-nortestosterone analogs and determine their affinity for binding to the ligand binding domain (LED) of human AR and their in vitro anti-androgen ability against a series of human prostate cancer cell lines. In Specific Aim 2. the best of each of the four classes of analogs will be coupled via their side chain to a synthetic ligand for FK-506 binding protein (i.e., denoted SLF) to produce bifunctional binding analogs which while tethered to the LBD of AR also binds FK-506 producing an adduct sterically bulky enough to prevent any AR co-activator binding. In Specific Aim 3. the SLF bifunctional analogs will be tested for their efficacy vs. casodex in vitro and in vivo against a series of human prostate cancers in an androgen ablated environment. To achieve these goals in a timely fashion, a team approach is reguired involving the collaboration of Dr. Oladapo Bakare of Howard University and Dr. John Isaacs of Johns Hopkins University. Dr. Bakare's expertise is in organic chemical synthesis and his laboratory will synthesize all of the proposed analogs. Dr. Isaacs' expertise is in tumor biology and chemical therapeutics focused particularly on prostate cancer, and his laboratory will perform all of the biochemical, and in vitro/in vivo evaluations of the newly synthesized compounds.