ANDROGEN SYNTHESIS INHIBITORS FOR PROSTATE CANCER

描述（由申请人提供）：该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化合物。我们的策略是找出能完全阻断雄激素的化合物。我们已经发现了一些有效的17 α -羟化酶/ c17,20 -裂解酶（CYP17）抑制剂。其中一些被发现有多种活动。一些抑制5a-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表征最好的三种化合物。该化合物对小鼠异种移植模型中雄激素依赖性肿瘤具有显著的抗肿瘤活性，并能显著降低雄激素水平。为了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期试验做准备，提出了以下具体目标。该项目的具体目标是：1。先导化合物的代谢研究：a.代谢预测模型，b.放射性标记抑制剂的合成，c.代谢研究；2. 设计和合成：a.现有抑制剂的类似物，以改善代谢稳定性和提高疗效；b.基于分子建模方法的非甾体抑制剂；3. 评价抑制17 α -羟化酶/ C17、20-裂解酶的类似物和新化合物，以及所有抑制5 α -还原酶I型和II型的有效抑制剂；4. 探讨CYP17抑制剂对前列腺癌细胞雄激素依赖性生长的影响；5. 通过结合和转录激活试验确定CYP17抑制剂是突变型或野生型雄激素受体的激动剂还是拮抗剂；和6。为了优化最有效的抑制剂在人类前列腺癌（LAPC-4和LNCaP雄激素依赖性肿瘤）小鼠异种移植模型中的抗肿瘤效果：a.确定有效剂量、计划和给药途径；b.比较先导抑制剂和去势对细胞凋亡的影响，以确定最佳化合物。

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.