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，这种形式的治疗是不能治愈的，最终疾病将以去势抵抗形式（也称为激素难治性或雄激素非依赖性）返回。一旦疾病是去势抵抗，生存时间约为两年之前，病人将死于他的疾病。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，必须知道一个靶点。我们的实验室已经确定了雄激素受体的N-末端结构域作为药物开发的新的治疗靶点。该靶点得到了数据的支持，这些数据显示，在不存在雄激素的情况下，雄激素受体的N-末端结构域通过替代途径被激活，并且靶向受体的该结构域在体内阻断肿瘤生长和进展。我们已经确定了两个结构无关的小分子（EPI-001和SINT 1）分离的海绵，抑制反式激活的N-末端结构域的雄激素受体。这些小分子具有体外（细胞培养）和体内（动物）特异性活性，可阻断增殖和雄激素受体活性，并降低去势抵抗性异种移植物的肿瘤负荷。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，需要完成一些项目，这里讨论了几个项目。Specific Aim 1将合成EPI-001的单一立体异构体或非手性衍生物，并在基于细胞的活性测定中进行测试，并制备合成的更稳定的SINT 1衍生物。具体目标2将描述EPI-001和SINT 1抑制AR NTD反式激活的分子机制。Specific Aim 3将测试SINT 1和EPI-001以及各种类似物在不同前列腺癌模型中的功效。虽然传统的治疗集中在雄激素受体通过其C-末端配体结合结构域的雄激素依赖性激活，我们的概念，阻断的N-末端结构域的雄激素受体的反式激活治疗晚期前列腺癌还没有得到解决。没有雄激素受体N-末端结构域的抑制剂，并且此类化合物将代表一类新的拮抗剂。在睾丸雄激素不存在的情况下，通过靶向N-末端结构域来抑制雄激素受体的转录活性以阻断肿瘤生长的能力为开发用于前列腺癌临床管理的雄激素受体拮抗剂提供了新的方向。 公共卫生相关性：一旦前列腺癌复发，就无法提供有效的治疗方法，患者将在大约两年内死于这种疾病。越来越多的证据支持去势复发性疾病的发生与影响雄激素受体功能的分子变化有因果关系的观点。在这里，我们建议开发针对雄激素受体的独特区域的小分子，这将延迟或阻止激素进展到前列腺癌的终末期。

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. PUBLIC HEALTH RELEVANCE: Once prostate cancer becomes castrate-recurrent there are no effective therapies that can be offered and the patient will succumb to his disease in approximately two years. There is mounting evidence supporting the concept that development of castrate-recurrent disease is causally related to molecular changes affecting the function of the androgen receptor. Here we propose to develop small molecules that target a unique region of the androgen receptor that will delay or prevent hormonal progression to the terminal stage of prostate cancer.