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

Johns Hopkins University, Baltimore MD

Investigators

Linked publications & trials

Abstract

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