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

完整项目 3：治疗前列腺癌的新型双功能抗雄激素药物

• 批准号: 7250612
• 负责人: JOHN Tod ISAACS
• 金额: $ 8.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250612
• 关键词: analog; androgens; clinical research; conformation; human; ligands; prostate neoplasms; proteins; university

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.

在前列腺癌的进展过程中，恶性细胞经历分子变化，其中 AR 与伙伴蛋白相互作用产生基因组和非基因组信号，从而允许它们 在雄激素消除产生的低循环血清 T 的情况下持续生长。因此，这些细胞 标准雄激素消除（即 LHRH+/-casodex）无法消除它们，并且它们最终会持续生长 杀死病人。这种致死率在美国的非裔美国男性中最高。到 解决这种健康差距，为此类雄激素消融抵抗患者开发有效的治疗方法是 本申请的重点。我们的工作假设是，为什么目前的雄性消融疗法是 功效有限，因为 AR 蛋白在未占据或与低分子结合时的构象 体重部分激动剂或拮抗剂，如 Casodex。可以通过共激活剂的结合“强制”取代 共阻遏物并经历完全激动剂构象的变化，诱导生长刺激信号传导。 因此，在雄激素消融失败的患者中阻断此类 AR 生长信号传导的新策略是 开发“大量双功能抗雄激素，与 AR 的配体结合域结合并在结构上锁定 AR 表面的 AF-2 结构域处于拮抗构象，不允许其 AF-2 结构域被“强制” 进入激动状态。因此具体目标1是设计并合成一系列苄基或烷基11β和 7α侧链-δ9-19-去甲睾酮类似物并测定它们与配体结合的亲和力 人AR的结构域（LED）及其对一系列人前列腺癌的体外抗雄激素能力 细胞系。在具体目标 2 中，四类类似物中每一类的最佳类似物将通过其侧链耦合 与 FK-506 结合蛋白的合成配体（即表示为 SLF）连接以产生双功能结合类似物 它虽然与 AR 的 LBD 相连，但也与 FK-506 结合，产生空间足够大的加合物 防止任何 AR 共激活剂结合。在具体目标 3 中，将测试 SLF 双功能类似物的性能 在雄激素消融的情况下，与 casodex 相比，体外和体内对抗一系列人类前列腺癌的功效 环境。为了及时实现这些目标，需要采用团队方法，包括 霍华德大学的 Oladapo Bakare 博士和约翰·霍普金斯大学的 John Isaacs 博士合作。 Bakare 博士的专业知识是有机化学合成，他的实验室将合成所有拟议的 类似物。 Isaacs 博士的专业知识是肿瘤生物学和化学疗法，特别关注前列腺 癌症，他的实验室将对新的癌症进行所有生化和体外/体内评估 合成的化合物。