Chimeric Inhibitors of Androgen Biosynthesis and Signaling

雄激素生物合成和信号转导的嵌合抑制剂

• 批准号: 9756670
• 负责人: Caleb D. Vogt
• 金额: $ 3.63万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-19 至 2021-02-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756670
• 关键词: 5 Alpha-Reductase Inhibitor; Acetates; Address; Agonist; Anabolism; Androgen Antagonists; Androgen Receptor; Androgens; Biology; CYP17A1 gene; CYP21A2 gene; Cancer Cell Growth; Castration; Cell Line; Chemicals; Collaborations; Computer Simulation; Coupling; Cytochrome P450; Development; Disease; Docking; Drug Targeting; Dutasteride; Edema; Enzymes; Generations; Goals; Hypertension; Hypokalemia; Interruption; Ketones; Lead; Libraries; Ligands; Malignant neoplasm of prostate; Medical; Metabolic; Metabolism; Michigan; Modification; North Carolina; Operative Surgical Procedures; Oranges; Oxidoreductase; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Positioning Attribute; Prodrugs; Production; Protein Isoforms; Quality of life; Reaction; Research; Research Personnel; Research Project Grants; Resistance development; Route; Series; Signal Transduction; Structure; Supervision; Testing; United States; Universities; abiraterone; analog; castration resistant prostate cancer; design; drug discovery; effective therapy; functional group; improved; pharmacophore; prostate cancer cell; stability testing; steroid hormone; treatment strategy; tumor

PROJECT ABSTRACT Chimeric Inhibitors of Androgen Biosynthesis and Signaling Androgens drive the progression of over 80% of prostate cancer tumors. Therefore, treatment strategies often use surgical or chemical castration to disrupt the signaling of these steroid hormones through the androgen receptor (AR). Despite the initial efficacy of such therapies, patients inevitably develop resistance leading to castration-resistant prostate cancer (CRPC), which is sustained by very low androgen levels in the body. Of the few drugs approved for this advanced and fatal stage of the disease, the prodrug abiraterone acetate is the only one designed to target cytochrome P450 17A1 (CYP17A1), an enzyme required for androgen production. In patients, abiraterone (the primary active agent) is converted into the more potent Δ4-abiraterone, which both inhibits CYP17A1 and antagonizes the AR. Unfortunately, Δ4-abiraterone does not significantly accumulate in patients. Instead, this metabolite is irreversibly modified by 5α-reductase into an AR agonist, which actually promotes prostate cancer cell growth (similar to endogenous androgens). In order to address this immediate medical need, the goal of this proposal is to design analogues of Δ4-abiraterone that avoid unwanted metabolism by 5α-reductase but still interrupt androgen biosynthesis and signaling at multiple points. To this end, the immediate objective is to replace the key metabolic liability of Δ4-abiraterone, while maintaining potency and enhancing selectivity at CYP17A1, one of the primary drug targets. Accordingly, the following aims will be pursued: (1a) replace the key metabolic liability of Δ4-abiraterone, (1b) improve the selectivity of synthesized analogues for CYP17A1, and (2) explore 3-pyridyl substituent effects on the polypharmacology of Δ4-abiraterone. The compounds described in this proposal are also designed to inhibit 5α-reductase and antagonize the AR, which is expected to lead to greater anti-tumor activity than Δ4-abiraterone itself. In collaboration with researchers from the University of Michigan-Ann Arbor and the University of North Carolina at Chapel Hill, some of the polypharmacology of the proposed compounds will be characterized against key drug targets of CRPC (i.e., CYP17A1, 5α-reductase, and the AR). If the immediate objective is achieved, this research project would demonstrate that mimics of the more potent Δ4-abiraterone can be rationally designed, facilitating the development of more effective treatments for advanced stage prostate cancer.

项目摘要 雄激素生物合成和信号传导的嵌合抑制剂 雄激素驱动超过80％的前列腺癌肿瘤的进展。因此，治疗策略经常 使用手术或化学cast割破坏通过雄激素的这些立体激素的信号传导 受体（AR）。尽管这种疗法的初始效率，但患者不可避免地会产生抗药性 耐castration-抗性前列腺癌（CRPC），体内雄激素水平很低。的 很少有药物批准为该疾病的这种高级和致命阶段，前药阿比里特酮是唯一的 一种旨在靶向细胞色素P450 17A1（CYP17A1），这是一种生产雄激素所需的酶。在 患者，阿比罗酮（主要的活性剂）被转化为较大的潜在Δ4-丙酮，这两者都 抑制CYP17A1并拮抗AR。不幸的是，在 患者。相反，该代谢物被5α-还原酶不可逆地修饰为AR激动剂，实际上 促进前列腺癌细胞的生长（类似于内源性雄激素）。为了解决这一立即解决 医疗需求，该提案的目的是设计Δ4-abiraterone的类似物，以避免新陈代谢 通过5α-还原酶，但仍在多个点中断雄激素生物合成和信号传导。为此， 直接目标是替代Δ4-丙酮酮的主要代谢责任，同时保持效力和 提高CYP17A1的选择性，这是主要药物靶标之一。根据，以下目标将是 追捕：（1a）替换Δ4-abiraterone的关键代谢责任，（1b）提高合成的选择性 CYP17A1的类似物和（2）探讨了3-吡啶基亚tit词对Δ4-abiraterone的多种药理学的影响。 该提案中描述的化合物还旨在抑制5α-还原酶并拮抗AR， 与Δ4-abiraterone本身相比，这预计会导致更大的抗肿瘤活性。与研究人员合作 来自密歇根大学 - 安阿伯分校和北卡罗来纳大学教堂山，一些 针对CRPC的关键药物靶标（即， CYP17A1，5α-还原酶和AR）。如果达到直接目标，该研究项目将 证明模仿更势Δ4-丙酮酮可以合理设计，以支持 开发晚期前列腺癌的更有效的治疗方法。