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转导的嵌合抑制剂 雄激素驱动超过80%的前列腺癌肿瘤的进展。因此，治疗策略往往 使用手术或化学阉割来破坏这些类固醇激素通过雄激素的信号传导， 受体（AR）。尽管这些疗法的初始疗效，但患者不可避免地产生耐药性，导致 去势抵抗性前列腺癌（CRPC），其由体内非常低的雄激素水平维持。的 很少有药物被批准用于这种疾病的晚期和致命阶段，前药醋酸阿比特龙是唯一的 一种设计用于靶向细胞色素P450 17 A1（CYP 17 A1），一种雄激素产生所需的酶。在 在患者中，阿比特龙（主要活性剂）转化为更有效的Δ4-阿比特龙， 抑制CYP 17 A1并拮抗AR。不幸的是，Δ4-阿比特龙不会显著地在小鼠中积累。 患者相反，这种代谢物被5α-还原酶不可逆地修饰为AR激动剂， 促进前列腺癌细胞生长（类似于内源性雄激素）。为了解决这一紧迫问题， 为了满足医疗需求，该提案的目标是设计Δ4-阿比特龙的类似物， 但仍然在多个点中断雄激素生物合成和信号传导。为此中央 直接目标是替代Δ4-阿比特龙的关键代谢倾向，同时保持效力， 增强对主要药物靶点之一CYP 17 A1的选择性。因此，将实现以下目标： 追求：（1a）取代Δ4-阿比特龙的关键代谢倾向，（1b）提高合成的选择性 CYP 17 A1的类似物，和（2）探索3-吡啶基取代基对Δ4-阿比特龙多药理学的影响。 该提案中描述的化合物还被设计为抑制5α-还原酶并拮抗AR， 预计其比Δ4-阿比特龙本身具有更大的抗肿瘤活性。与研究人员合作， 来自密歇根大学安娜堡分校和查佩尔山的北卡罗来纳州大学的一些研究人员， 所提出的化合物的多药理学将针对CRPC的关键药物靶标（即， CYP 17 A1、5α-还原酶和AR）。如果近期目标得以实现，该研究项目将 证明可以合理地设计更有效的Δ4-阿比特龙的模拟物，从而促进 为晚期前列腺癌开发更有效的治疗方法。