Novel compounds that inhibit transactivation of N-terminal domain of the androgen

描述（由申请人提供）：晚期前列腺癌的治疗涉及降低患者的睾酮（雄激素）水平。不幸的是，这种疗法不能治愈，最终这种疾病会以去势抵抗形式复发（也称为激素难治性或雄激素非依赖性）。一旦这种疾病具有去势抵抗性，在患者死于疾病之前，存活时间大约为两年。目前没有任何有效的治疗方法可用于这些患者。为了开发新的治疗方法，必须知道一个目标。我们的实验室已经确定了雄激素受体的n端结构域作为药物开发的新治疗靶点。数据显示，雄激素受体的n端结构域在缺乏雄激素的情况下通过其他途径被激活，并且靶向受体的n端结构域可阻断体内肿瘤的生长和进展，这一靶点得到了支持。我们从海绵中分离出两个结构无关的小分子（EPI-001和SINT1），它们抑制雄激素受体n端结构域的转激活。这些小分子在体外（细胞培养）和体内（动物）具有特异性活性，可阻断增殖和雄激素受体活性，减少去势抵抗异种移植物的肿瘤负担。我们的最终目标是将这些化合物或其结构衍生物投入临床试验。为了实现这一目标，需要完成许多项目，这里讨论了其中几个项目。Specific Aim 1将合成并测试EPI-001的单一立体异构体或非手性衍生物的细胞活性，并合成更稳定的SINT1衍生物。特异性目标2将描述EPI-001和SINT1抑制AR NTD转激活的分子机制。特异性Aim 3将测试SINT1和EPI-001以及各种类似物在不同前列腺癌模型中的疗效。虽然传统的治疗方法主要集中在雄激素受体通过其c端配体结合域的雄激素依赖性激活，但我们阻断雄激素受体n端结构域的反激活以治疗晚期前列腺癌的概念尚未得到解决。目前还没有雄激素受体n端结构域的抑制剂，这类化合物将代表一类新的拮抗剂。在缺乏睾丸雄激素的情况下，通过靶向n端结构域抑制雄激素受体的转录活性来阻断肿瘤生长的能力为开发雄激素受体拮抗剂用于前列腺癌的临床治疗提供了新的方向。

DESCRIPTION (provided by applicant): Treatment for advanced prostate cancer involves the reduction of the patients' levels of testosterone (androgen). Unfortunately, this form of therapy is not curative and eventually the disease will return in a castrate resistant form (also called hormone refractory or androgen-independent). Once the disease is castrate resistant, the survival time is approximately two years before the patient will succumb to his disease. There are not any effective therapies currently available for these patients. To develop new therapies, a target must be known. Our laboratory has 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 the N-terminal domain of the androgen receptor is activated by alternative pathways in the absence of androgens and targeting this domain of the receptor blocks tumor growth and progression in vivo. We have identified two structurally unrelated small molecules (EPI-001 and SINT1) isolated from marine sponges that inhibit transactivation of N-terminal domain of the androgen receptor. These small molecules have in vitro (cell culture) and in vivo (animal) specific activity to block proliferation and androgen receptor activity, and decrease tumor burden of castrate-resistant xenografts. Our ultimate goal is to move these compounds, or their structural derivatives, into clinical trials. To meet this goal a number of items need to be fulfilled and several are addressed here. Specific Aim 1 will synthesize and test single stereoisomers or achiral derivatives of EPI-001 in cell based assays for activity and make a synthetic, and more stable derivative of SINT1. Specific Aim 2 will delineate the molecular mechanisms involved in EPI-001 and SINT1 inhibition of transactivation of the AR NTD. Specific Aim 3 will test the efficacy of SINT1 and EPI-001 and various analogues in different models of prostate cancer. While conventional therapy has concentrated on androgen-dependent activation of the androgen receptor through its C-terminal ligand-binding domain, our concept of blocking transactivation of the N-terminal domain of the androgen receptor for the therapy of advanced prostate cancer has not been previously addressed. There are no inhibitors to the N-terminal domain of the androgen receptor and such compounds would represent a new class of antagonists. The capability to inhibit transcriptional activity of the androgen receptor by targeting the N-terminal domain to block tumor growth in the absence of testicular androgen presents a new direction for the development of antagonists to the androgen receptor for the clinical management of prostate cancer.