Delineating the mechanisms of androgen receptor activation function-1 antagonists for development of novel prostate cancer therapeutics

晚期前列腺癌的治疗包括降低患者的睾酮水平 (雄激素)通过手术和药物去势。不幸的是，这种形式的治疗不能治愈 最终，这种疾病将以耐阉割的形式卷土重来。一旦这种疾病对去势产生抵抗力， 患者的生存时间大约是两年后才会死于他的疾病。开发新的 治疗，目标必须是知道的。我们实验室鉴定出雄激素受体的N-末端结构域为 药物开发的新治疗靶点。这一目标得到了数据的支持，数据显示，以此为目标 受体的结构域在体内阻止肿瘤的生长和进展。我们已经确定了EPI和辛托卡胺 作为雄激素受体N末端结构域的第一类拮抗剂。这两种化合物都是特定的 并与雄激素受体的N-末端结构域结合。然而，它们似乎有不同的机制 行动的一部分。现在我们利用这一进展，在目标1中，我们建议表征 导致雄激素受体活性抑制的辛托卡胺。目标2将确定分子 雄激素抑制基因可能提供潜在获得性耐药线索的机制 联合疗法和药效学生物标记物。目标3将阐明结合特性。目标4 将使用人类前列腺癌异种移植在体内测试化合物和单一疗法的组合。 这些新型雄激素受体N-末端结构域的抑制剂是仅有的可用于N- 任何类固醇激素受体的末端结构域，代表一类新的雄激素受体拮抗剂。 所有产生的数据都将是新的，并为耐药的潜在机制提供新的见解 开发，并揭示可能的药效学标志物。

Treatment for advanced prostate cancer involves the reduction of the patients' levels of testosterone (androgen) by surgical and pharmacological castration. Unfortunately, this form of therapy is not curative and eventually the disease will return in a castration resistant form. Once the disease is castration resistant, the survival time is approximately two years before the patient will succumb to his disease. To develop new therapies, a target must be known. Our laboratory identified the N-terminal domain of the androgen receptor as a novel therapeutic target for drug development. This target is supported by data showing that targeting this domain of the receptor blocks tumor growth and progression in vivo. We have identified EPI and sintokamide as first in class of antagonists to androgen receptor N-terminal domain. These compounds were both specific and bind to the N-terminal domain of androgen receptor. However, they appear to have different mechanisms of action. Now we draw on this progress and in Aim 1 we propose to characterize the mechanism of sintokamide that causes inhibition of androgen receptor activity. Aim 2 will determine the molecular mechanisms of androgen-repressed genes to yield clues about potential acquired resistance, possible combination therapies, and pharmacodynamic biomarkers. Aim 3 will elucidate binding characteristics. Aim 4 will test combinations of compounds versus monotherapies in vivo using human prostate cancer xenografts. These novel inhibitors to the androgen receptor N-terminal domain are the only ones available for an N- terminal domain of any steroid hormone receptor and represent a new class of androgen receptor antagonists. All data generated will be novel and provide new insight into potential mechanisms of resistance, drug development, and reveal possible pharmacodynamic markers.