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

抑制雄激素 N 末端结构域反式激活的新型化合物

• 批准号: 8006189
• 负责人: MARIANNE D SADAR
• 金额: $ 22.27万
• 依托单位: BRITISH COLUMBIA CANCER AGENCY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006189
• 关键词: Address; Affect; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Animals; Biological Assay; C-terminal; CWR22Rv1; Castration; Cell Culture Techniques; Cells; Chemistry; Clinical Management; Clinical Trials; Data; Development; Disease; Drug Delivery Systems; Gene Expression; Genes; Global Change; Goals; Hormonal; Hormones; In Vitro; Investigation; Knowledge; LNCaP; Laboratories; Lead; Ligand Binding; Ligand Binding Domain; Ligands; Malignant neoplasm of prostate; Marines; Mediating; Modeling; Molecular; Mus; N-terminal; Nuclear; Orphan; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Play; Porifera; Prevention; Proteins; Receptor Gene; Recurrence; Recurrent disease; Refractory; Resistance; Role; Serum; Signal Pathway; Specificity; Staging; Stereoisomer; Steroid Receptors; Testing; Testosterone; Therapeutic; Time; Tissues; Toxic effect; Transactivation; Tumor Burden; Work; Xenograft procedure; analog; base; cancer cell; conventional therapy; cytotoxicity; drug development; effective therapy; efficacy testing; in vivo; inhibitor/antagonist; meetings; multidisciplinary; new therapeutic target; novel; prevent; protein protein interaction; public health relevance; receptor; research study; small molecule; steroid hormone; therapy development; transcription factor; tumor; tumor growth

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.

描述(申请人提供)：晚期前列腺癌的治疗包括降低患者的睾酮(雄激素)水平。不幸的是，这种形式的治疗不能治愈，最终这种疾病会以去势抵抗的形式复发(也称为激素抵抗或雄激素非依赖性)。一旦这种疾病具有去势抵抗力，患者大约两年后就会死于自己的疾病。目前还没有任何有效的治疗方法可用于这些患者。要开发新的治疗方法，必须知道目标。我们的实验室已经确定雄激素受体的N端结构域是药物开发的一个新的治疗靶点。有数据表明，在没有雄激素的情况下，雄激素受体的N末端区域可以通过其他途径激活，并以该受体区域为靶点阻止体内肿瘤的生长和进展，这一点得到了支持。我们已经确定了两个结构上无关的小分子(EPI-001和SINT1)，它们是从海绵中分离出来的，它们抑制雄激素受体N末端结构域的反式激活。这些小分子在体外(细胞培养)和体内(动物)都具有特异的活性，可以阻断细胞增殖和雄激素受体活性，并降低去势耐受异种移植的肿瘤负担。我们的最终目标是将这些化合物或其结构衍生品投入临床试验。为了实现这一目标，需要完成一些项目，其中有几个项目在此阐述。特定目标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分析中进行测试，并合成更稳定的SINT1衍生物。具体目标2将描述EPI-001和SINT1抑制AR NTD反式激活的分子机制。特殊目标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的C末端配体结合域的雄激素依赖性激活，但我们的概念是阻断雄激素受体的N末端区域的反式激活来治疗晚期前列腺癌，这一概念以前还没有被提出过。目前还没有雄激素受体N-末端结构域的抑制剂，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-末端结构域来抑制雄激素受体的转录活性以阻止肿瘤生长的能力，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。 公共卫生相关性：一旦前列腺癌变得去势复发，就没有有效的治疗方法可以提供，患者将在大约两年内死于自己的疾病。越来越多的证据支持这样一种观点，即去势复发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。在这里，我们建议开发以雄激素受体的一个独特区域为靶点的小分子，以延缓或阻止激素进展到前列腺癌的晚期。