ANDROGEN SYNTHESIS INHIBITORS FOR PROSTATE CANCER

描述(申请人提供)：该项目的目标是开发具有可能对雄激素依赖型前列腺癌提供有效抗肿瘤活性的特征的化合物。我们的策略是识别能够完全阻断雄激素的化合物。我们已经发现了许多有效的17α-羟基酶/C17，20-裂解酶(CYP17)的抑制剂。其中几个被发现有多个活动。有些抑制5a-还原酶和/或是抗雄激素。VN/85-1、VN/87-1和L-39是迄今为止效力最强、表征最好的三种化合物。这些化合物对小鼠异种移植模型中的雄激素依赖性肿瘤具有显着的抗肿瘤活性，并使雄激素水平显着降低。为了开发活性最高的抑制剂，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，以及c.代谢研究；2.设计和合成：a.用于改善代谢稳定性和增加疗效的现有抑制剂的类似物和b.基于分子模拟方法的非甾体类抑制剂；3.评价类似物和新化合物对5α-还原酶I和II类的抑制作用；4.确定细胞色素P17抑制剂对前列腺癌雄激素依赖性生长的影响；5.通过结合和转录激活分析确定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；以及6.在人前列腺癌(LAPC-4和LNCaP雄激素依赖性肿瘤)小鼠移植瘤模型中，优化最有效的抑制剂的抗肿瘤效果：a.确定有效剂量、给药程序和给药途径；b.比较铅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.