Adrenal Androgen Blockade for Metastic Prostate Cancer

描述(由申请人提供)： 前列腺癌是美国男性癌症死亡的第二大常见原因。转移性前列腺癌的一线治疗是抑制睾丸雄激素合成。来自肾上腺的睾酮前体是肾上腺雄激素，可能占前列腺雄激素负荷的25%，但目前还没有安全有效的药物来抑制肾上腺雄激素的产生。核受体是新药靶点的丰富来源，通过小分子与保守的配体结合域相互作用来控制基因表达。孤儿核受体SF-1(类固醇生成因子-I)调节类固醇激素的产生和肾上腺功能，主要在类固醇生成组织中表达。该项目的目标是寻找通过SF-1抑制肾上腺雄激素合成的小分子药物。在临床上，这种治疗药物可以与目前的睾丸雄激素抑制治疗相结合，实现完全的雄激素抑制，并显著推迟雄激素非依赖性前列腺癌的出现。主要目的是：(1)优化基于细胞的受体基因激活和间接结合分析，以筛选SF-1化合物；(2)筛选靶向化学文库，以鉴定结构多样化的HITS；(3)通过集中化学合成寻找更有效的SF-1配体；(4)表征SF-1配体对类固醇激素合成的调节。在第二阶段，将合成高亲和力和特异性的拮抗剂配体，以抑制肾上腺雄激素，并开发用于动物试验的先导化合物。将与制药业的一个主要合作伙伴一起进行商业化的临床前和临床测试。

DESCRIPTION (provided by applicant): Prostate cancer is the second most common cause of cancer death among men in the United States. The first-line therapy for metastatic prostate cancer is suppression of testicular androgen synthesis. Testosterone precursors derived from the adrenal gland, the adrenal androgens, may contribute as much as 25% of the androgen load in the prostate, but there is no safe and effective drug which inhibits adrenal androgen production. The nuclear receptors, a rich source of new drug targets, control gene expression through interaction of small molecules with a conserved ligand-binding domain. The orphan nuclear receptor SF-1 (steroidogenic factor-I) regulates steroid hormone production and adrenal gland function and is mainly expressed in steroidogenic tissues. The goal of this project is to identify small molecule drugs that suppress adrenal androgen synthesis through SF-1. In the clinic, such a therapeutic drug could be combined with current testicular androgen suppression therapies to achieve total androgen suppression and significantly delay the appearance of the androgen independent form of prostate cancer. Key aims are to: (1) Optimize cell-based receptor gene activation and indirect binding assays for compound screening of SF-1; (2) screen targeted chemical libraries to identify structurally diverse hits; (3) identify more potent SF-1 ligands through focused chemical synthesis and (4) characterize SF-1 ligand regulation of steroid hormone synthesis in steroidogenic cell lines. In Phase II, antagonist ligands of high affinity and specificity will be synthesized that suppress adrenal androgens, and lead compounds developed for animal testing. Preclinical and clinical testing for commercialization will be carried out with a major partner in the pharmaceutical industry.