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

描述雄激素受体激活功能-1拮抗剂用于开发新型前列腺癌疗法的机制

• 批准号: 9234913
• 负责人: MARIANNE D SADAR
• 金额: $ 26.08万
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234913
• 关键词: Affect; Androgen Antagonists; Androgen Receptor; Androgens; Binding; Binding Sites; Biological Markers; Blood; CYP17A1 gene; Castration; Characteristics; Chemistry; Clinical Trials; Combined Modality Therapy; Data; Development; Disease; Disease Resistance; Gene Expression; Generations; Genes; Genetic Transcription; Global Change; Hormonal; Hormones; Human; Intercept; Laboratories; Length; Ligand Binding Domain; Ligands; Malignant neoplasm of prostate; Maps; Molecular; N-terminal; Nomenclature; Operative Surgical Procedures; Orchiectomy; Orphan; Patients; Pharmacologic Substance; Pharmacology; Prevention; Prostate-Specific Antigen; Proteins; RNA Splicing; Receptor Activation; Recurrence; Refractory; Research; Resistance; Resources; Serum; Structure; Testing; Testosterone; Therapeutic; Time; Tissues; Transactivation; Variant; Work; Xenograft procedure; analog; base; castration resistant prostate cancer; curative treatments; derepression; drug development; drug mechanism; experimental study; hormone therapy; in vivo; inhibitor/antagonist; innovation; insight; multidisciplinary; new therapeutic target; novel; novel therapeutics; pharmacodynamic biomarker; preclinical study; prevent; programs; protein protein interaction; receptor; resistance mechanism; small molecule; small molecule inhibitor; steroid hormone; steroid hormone receptor; therapy development; transcription factor; tumor growth; tumor progression

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.

晚期前列腺癌的治疗包括降低患者的睾丸激素水平 （雄激素）通过手术和药物阉割。不幸的是，这种形式的治疗不是治愈性的， 最终这种疾病会以一种抵抗阉割的形式复发。一旦疾病对去势抵抗， 病人的存活时间大约是两年，然后才死于他的疾病。开发新 治疗，必须知道目标。我们的实验室鉴定了雄激素受体的N-末端结构域， 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， 受体的结构域在体内阻断肿瘤生长和进展。我们已经确认了肾上腺素和辛托卡胺 作为雄激素受体N-末端结构域的第一种拮抗剂。这些化合物都是 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， 的行动。现在，我们利用这一进展，在目标1中，我们提出表征 引起雄激素受体活性抑制的辛托卡胺。目标2将确定分子 雄激素抑制基因的机制产生潜在的获得性抗性的线索，可能 联合治疗和药效学生物标志物。目的3将阐明结合特性。目标4 将使用人前列腺癌异种移植物在体内测试化合物组合与单一疗法。 这些雄激素受体N-末端结构域的新型抑制剂是唯一可用于N-末端结构域的抑制剂。 任何类固醇激素受体末端结构域，代表一类新的雄激素受体拮抗剂。 产生的所有数据将是新颖的，并提供新的见解的潜在机制的耐药性，药物 开发，并揭示可能的药效学标志物。