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: 7939596
• 负责人: JOHN Tod ISAACS
• 金额: $ 14.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7939596
• 关键词: AF2; AR gene; Ablation; Address; Affinity; African American; Agonist; Androgen Antagonists; Androgen Receptor; Androgens; Bicalutamide; Binding; Binding Proteins; Biochemical; Cancer Center; Cells; Chemicals; Collaborations; Coupled; Dependence; Environment; Epithelial Cells; Evaluation; Genomics; Goals; Growth; Human; In Vitro; Laboratories; Ligand Binding Domain; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular; Molecular Conformation; Molecular Weight; Nandrolone; Organic Chemicals; PC3 cell line; Patients; Prostate; Prostatic Epithelium; Proteins; Receptor Signaling; Regulation; Resistance; Series; Serum; Side; Signal Pathway; Signal Transduction; Stromal Cells; Surface; Testing; Therapeutic; Tumor Biology; United States; Universities; Work; adduct; analog; autocrine; cancer cell; chemical synthesis; design; effective therapy; extracellular; gain of function; health disparity; in vivo; killings; male; non-genomic; novel; novel strategies; paracrine; prevent; receptor

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，恶性细胞发生分子变化，其中AR 与伴侣蛋白相互作用以生成基因组和非基因组信号传导，这使它们 在雄激素消融产生的低循环血清T存在下，持续生长。因此，这些细胞 标准雄激素消融（即LHRH +/- casodex）并没有消除其连续生长 杀死病人。在我们在美国境内的非裔美国男性中，这种杀伤力最高。到 解决了这种健康差异，为这种抗雄激素消融患者开发有效的疗法是 本应用程序的重点。我们的工作假设是为什么现在的Androoen消融疗法是 有限的功效，因为当无占用或结合的BV低分子时AR蛋白的构象 重量部分激动剂或拮抗剂，例如casodex。可以通过联合激活剂的结合来“强迫” 共抑制剂并经历了诱导生长刺激信号传导的全部激动剂构象的变化。 因此，在雄激素消融失败的患者中阻止这种AR生长信号传导的新型策略是 开发“笨重的双功能抗雄激素，这些抗雄激素与AR和结构锁定的配体结合结构域结合 AR表面以拮抗剂构型的AF-2结构域不允许“强制”其AF-2结构域 进入激动剂国家。因此，具体目的1是设计和合成一系列苄基或烷基11Beta，以及 7Alpha侧链 - 戴尔塔19-19-北植物类似物，并确定其与配体结合结合的亲和力 人类AR的域（LED）及其对一系列人前列腺癌的体外抗雄激素能力 细胞系。在特定的目标2中。四类类似物中的每一个中最好的最好的将通过其侧链耦合 到FK-506结合蛋白（即表示SLF）的合成配体以产生双功能结合类似物 虽然将其束缚在AR的LBD上也可以结合FK-506，从而产生了足够笨重的加合物 防止任何AR共激活器结合。在特定的目标3中。SLF双功能类似物将进行测试 在体外和体内疗效与casodex在雄激素消融中的一系列人类前列腺癌 环境。为了及时实现这些目标，团队的方法正在涉及 霍华德大学Oladapo Bakare博士和约翰·霍普金斯大学的约翰·艾萨克斯博士的合作。 Bakare博士的专业知识是有机化学合成，他的实验室将综合所有建议的 类似物。 Isaacs博士的专业知识是肿瘤生物学和化学治疗剂，尤其是前列腺 癌症和他的实验室将对新近的所有生化/体外评估进行所有生化/体外评估 合成化合物。