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涉及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，这种疗法没有疗效，而且 最终这种疾病会以去势抵抗的形式复发。一旦疾病具有去势抵抗性， 患者死于疾病之前的生存时间约为两年。开发新的 治疗时，必须知道目标。我们的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。该目标得到了数据的支持，表明针对该目标 该受体的结构域可阻断体内肿瘤的生长和进展。我们已经鉴定出 EPI 和辛托卡胺 作为第一类雄激素受体 N 末端结构域拮抗剂。这些化合物都是特定的 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 的行动。现在，我们利用这一进展，在目标 1 中，我们建议描述以下机制的特征： 辛托卡酰胺会抑制雄激素受体活性。目标 2 将确定分子 雄激素抑制基因的机制可提供有关潜在获得性耐药性的线索，可能 联合疗法和药效生物标志物。目标 3 将阐明结合特征。目标 4 将使用人类前列腺癌异种移植物在体内测试化合物组合与单一疗法的比较。 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的末端结构域，代表一类新的雄激素受体拮抗剂。 生成的所有数据都将是新颖的，并为耐药性、药物的潜在机制提供新的见解 开发，并揭示可能的药效标记物。