ANDROGEN SYNTHESIS INHIBITORS FOR PROSTATE CANCER

前列腺癌的雄激素合成抑制剂

• 批准号: 7266871
• 负责人: ANGELA M. BRODIE
• 金额: $ 31.68万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-23 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7266871
• 关键词: Agonist; Androgen Antagonists; Androgen Receptor; Androgens; Apoptosis; Binding; Biological Assay; CYP17A1 gene; Castration; Characteristics; Dose; Figs - dietary; Goals; Growth; LNCaP; Lead; Lyase; Malignant neoplasm of prostate; Metabolic; Metabolism; Mixed Function Oxygenases; Mus; Numbers; Oxidoreductase; Phase I Clinical Trials; Prostate; Radiolabeled; Route; Schedule; Transcriptional Activation; Xenograft Model; analog; base; cancer cell; design; improved; inhibitor/antagonist; metabolic abnormality assessment; molecular modeling; mutant; preclinical study; predictive modeling; radiotracer; tumor

DESCRIPTION (provided by applicant): The goal of this project is to develop compounds with characteristics that are likely to provide effective antitumor activity against androgen dependent prostatic cancer. Our strategy is to identify compounds, which achieve total androgen blockade. We have discovered a number of potent inhibitors of 17alpha-hydroxylase/C17,20-lyase (CYP17). Several of these were found to have multiple activities. Some inhibit 5a- reductase and/or are antiandrogens. VN/85-1, VN/87-1, and L-39 are the three most potent and best characterized compounds to date. The compounds have significant antitumor activity in androgen dependent tumors in mouse xenograft models and cause marked reduction in androgen levels. The following specific aims are proposed in order to develop the most active inhibitors and complete preclinical studies of the lead compounds L-39, VN/85-1, and VN/87-1 and prepare them for Phase I trials. The Specific Aims of the project are: 1. Metabolic studies of lead compounds: a. Predictive models of metabolism, b. Synthesis of radiolabeled inhibitors, and c. Metabolic studies; 2. To design and synthesize: a. Analogs of current inhibitors to improve metabolic stability and increase efficacy and b. Non-steroidal inhibitors based on a molecular modeling approach; 3. To evaluate analogs and new compounds for inhibition of 17alpha-hydroxylase/ C17,20-lyase and all potent inhibitors for 5alpha -reductase Type I and Type II inhibition; 4. To determine the effects of the CYP17 inhibitors on androgen dependent growth in prostate cancer cells; 5. To determine whether the CYP17 inhibitors are agonists or antagonists of mutant or wild type androgen receptors using binding and transcriptional activation assays; and 6. To optimize the antitumor efficacy of the most potent inhibitors in mouse xenograft models with human prostate cancers (LAPC-4 and LNCaP androgen dependent tumors): a. Determine effective doses, scheduling, and route of administration and b. Compare the effect of lead inhibitors and castration on apoptosis to identify the best compound.

描述（由申请方提供）：本项目的目标是开发具有可能对雄激素依赖性前列腺癌提供有效抗肿瘤活性的特征的化合物。我们的策略是确定化合物，实现完全雄激素阻断。我们已经发现了许多有效的17 α-羟化酶/C17，20-裂解酶（CYP 17）抑制剂。其中一些被发现有多种活动。一些抑制5 α-还原酶和/或抗雄激素。VN/85-1、VN/87-1和L-39是迄今为止最有效和最好表征的三种化合物。该化合物在小鼠异种移植模型中的雄激素依赖性肿瘤中具有显著的抗肿瘤活性，并引起雄激素水平的显著降低。提出了以下具体目标，以开发最具活性的抑制剂，完成先导化合物L-39、VN/85-1和VN/87-1的临床前研究，并为I期试验做好准备。该项目的具体目标是：1。先导化合物的代谢研究：a.代谢的预测模型，B。放射性标记的抑制剂的合成，和c.代谢研究; 2.设计和合成：a.改善代谢稳定性和增加功效的当前抑制剂的类似物，和B.基于分子模拟方法的非甾体抑制剂; 3.评价用于抑制17 α-羟化酶/ C17，20-裂解酶的类似物和新化合物以及用于抑制5 α-还原酶I型和II型的所有有效抑制剂; 4.确定CYP 17抑制剂对前列腺癌细胞中雄激素依赖性生长的影响; 5.使用结合和转录激活测定来确定CYP 17抑制剂是否是突变型或野生型雄激素受体的激动剂或拮抗剂;以及6.为了优化最有效的抑制剂在具有人前列腺癌（LAPC-4和LNCaP雄激素依赖性肿瘤）的小鼠异种移植物模型中的抗肿瘤功效：确定有效剂量、时间表和给药途径，以及B.比较铅抑制剂和去势对细胞凋亡的影响，确定最佳化合物。