During the progression of prostatic cancer, malignant cells undergo molecular changes in which ARinteracts with partner proteins to generate genomic as well as non-genomic signaling which allows theircontinuing growth in the presence of low circulating serum T produced by androgen ablation. Thus, these cellsare not eliminated by standard androgen ablation (i.e.,LHRH+/-casodex) and their continuous growth eventuallykills the patient. Such lethality is highest among our African-American males within the United States. Toaddress this health disparity, developing effective therapy for such androgen ablation resistant patients is thefocus of the present application. Our working hypothesis is that why present androoen ablation therapy is oflimited efficacy because the conformation of the AR protein when either unoccupied or bound bv low molecularweight partial agonist or antagonist, like Casodex. can be 'forced' by the binding of co-activators to displaceco-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 todevelop 'bulky bifunctional anti-androgens which bind to the ligand binding domain of AR and structurally lockthe 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 and7alpha side chain-delta9-19-nortestosterone analogs and determine their affinity for binding to the ligand bindingdomain (LED) of human AR and their in vitro anti-androgen ability against a series of human prostate cancercell lines.
In Specific Aim 2. the best of each of the four classes of analogs will be coupled via their side chainto a synthetic ligand for FK-506 binding protein (i.e., denoted SLF) to produce bifunctional binding analogswhich while tethered to the LBD of AR also binds FK-506 producing an adduct sterically bulky enough toprevent any AR co-activator binding.
In Specific Aim 3. the SLF bifunctional analogs will be tested for theirefficacy vs. casodex in vitro and in vivo against a series of human prostate cancers in an androgen ablatedenvironment. To achieve these goals in a timely fashion, a team approach is reguired involving thecollaboration 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 proposedanalogs. Dr. Isaacs' expertise is in tumor biology and chemical therapeutics focused particularly on prostatecancer, and his laboratory will perform all of the biochemical, and in vitro/in vivo evaluations of the newlysynthesized compounds.
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