Chimeric Inhibitors of Androgen Biosynthesis and Signaling

项目摘要 雄激素生物合成和信号转导的嵌合抑制物 雄激素推动了超过80%的前列腺癌肿瘤的进展。因此，治疗策略往往 使用手术或化学去势来干扰这些类固醇激素通过雄激素的信号传递 受体(AR)。尽管这种疗法最初是有效的，但患者不可避免地会产生抵抗力，导致 耐阉割前列腺癌(CRPC)，由体内非常低的雄激素水平维持。中的 很少有药物被批准用于这种晚期和致命的疾病，前药醋酸阿比特龙是唯一的 一种是针对细胞色素P450 17A1(CYP17A1)的设计，细胞色素P450 17A1是产生雄激素所需的一种酶。在……里面 患者，阿比特龙(主要活性物质)被转化为更有效的Δ4-阿比特龙，这两种药物 抑制细胞色素P17A1，拮抗AR。不幸的是，Δ4-阿比特龙在体内没有显著累积。 病人。相反，这种代谢物被5α还原酶不可逆地修饰成AR激动剂，实际上 促进前列腺癌细胞生长(类似于内源性雄激素)。为了解决这个紧迫的问题 根据医学需要，该方案的目标是设计Δ4-阿比特龙的类似物，以避免不必要的代谢 通过5α-还原酶，但仍在多个点中断雄激素的生物合成和信号转导。为此， 近期目标是取代Δ4-阿比特龙的关键代谢缺陷，同时保持效力和 提高主要药物靶点之一的CYP17A1的选择性。相应地，以下目标将是 追求：(1a)取代Δ的关键代谢缺陷4-阿比特龙，(1b)提高合成的选择性 (2)探讨3-吡啶取代基对Δ-4-阿比特酮多药理作用的影响。 本提案中描述的化合物还被设计成抑制5α还原酶并拮抗AR， 这有望导致比Δ4-阿比特龙本身更强的抗肿瘤活性。与研究人员合作 来自密歇根大学安娜堡分校和北卡罗来纳大学教堂山分校的一些 建议化合物的多重药理学将对照CRPC的关键药物靶点进行表征(即， 细胞色素P17A1、5-α-还原酶和AR)。如果眼前的目标实现，这项研究项目将 证明可以合理设计更有效的Δ4-阿比特龙的模拟物，促进 开发更有效的治疗晚期前列腺癌的方法。

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.