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

在前列腺癌的发展过程中，恶性细胞经历了AR 与伙伴蛋白相互作用，产生基因组和非基因组信号，从而使他们的 在雄激素消融产生的低循环血清T存在的情况下持续生长。因此，这些细胞 不能通过标准的雄激素消融(即LHRH+/-Casodex)和它们的持续生长最终消除 杀死病人。这种致命性在美国境内的非裔美国男性中是最高的。至 解决这种健康差距，为这种雄激素消融抵抗的患者开发有效的治疗方法是 本申请的焦点。我们的工作假设是，为什么现在的雄激素消融疗法是 药效有限，因为AR蛋白在未被占据或结合的低分子时的构象 重量部分激动剂或拮抗剂，如Casodex。可以通过共激活剂的结合来“强迫”置换 共抑制物，并经历一个完整的激动剂构象诱导生长刺激信号的变化。 因此，在雄激素消融失败的患者中阻断这种AR生长信号的一个新策略是 开发与AR配体结合域结合并在结构上锁定的大体积双功能抗雄激素 拮抗剂构象中AR表面的AF-2结构域不允许其AF-2结构域被“强迫” 进入激动者状态。因此，专门的目标1是设计和合成一系列的苄基或烷基11β和 7α侧链-Delta9-19-去甲睾酮类似物，并确定它们与配体结合的亲和力 人AR结构域(LED)及其体外抗前列腺癌作用 细胞系。在特定的目标2.四类类似物中最好的将通过它们的侧链偶联 涉及FK-506结合蛋白的合成配体(即，记为SLF)以产生双功能结合类似物 在与AR的LBD结合时，它还与FK-506结合，产生空间上足够大的加合物 防止任何AR共激活剂结合。在具体目标3.将测试SLF双功能类似物的 雄激素治疗前列腺癌的体内外疗效比较 环境。为了及时实现这些目标，需要一种团队方法，包括 霍华德大学的奥拉博·巴卡雷博士和约翰·霍普金斯大学的约翰·艾萨克斯博士的合作。 巴卡雷博士的专长是有机化学合成，他的实验室将合成所有提议的 类比。艾萨克斯博士的专长是肿瘤生物学和化学疗法，尤其是前列腺癌。 癌症，他的实验室将进行所有的生化和体外/体内评估新的 合成化合物。

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.