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首页> 外文期刊>Nature reviews. Urology >CYP17 inhibitors - Abiraterone, C17,20-lyase inhibitors and multi-targeting agents
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CYP17 inhibitors - Abiraterone, C17,20-lyase inhibitors and multi-targeting agents

机译：CYP17抑制剂-阿比特龙，C17,20裂解酶抑制剂和多靶标药物

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As the first in class steroid 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor, abiraterone acetate (of which the active metabolite is abiraterone) has been shown to improve overall survival in patients with castration-resistant prostate cancer (CRPC) - in those who are chemotherapy-naive and those previously treated with docetaxel. Furthermore, the clinical success of abiraterone demonstrated that CRPC, which has previously been regarded as an androgen-independent disease, is still driven, at least in part, by androgens. More importantly, abiraterone is a 'promiscuous' drug that interacts with a number of targets, which dictate its clinical benefits and adverse effects profile. Besides CYP17 inhibition, abiraterone acts as an antagonist to the androgen receptor and inhibits 3β-hydroxysteroid dehydrogenase - two effects that potentially contribute to its antitumour effects. However, the inhibition of the 17α-hydroxylase activity of CYP17, CYP11B1 and a panel of hepatic CYP enzymes leads to adverse effects and toxicities that include secondary mineralocorticoid excess. Abiraterone is also associated with increased incidence of cardiac disorders. Under such circumstances, development of new CYP17 inhibitors as an additional line of defence is urgently needed. To achieve enhanced clinical benefits, new strategies are being explored that include selective inhibition of the C17,20-lyase activity of CYP17 and multi-targeting strategies that affect androgen synthesis and signalling at different points. Some of these strategies - including the drugs orteronel, VT-464 and galeterone - are supported by preclinical data and are being explored in the clinic.
机译：作为首个类固醇17α-羟化酶/ C17,20-裂解酶（CYP17）抑制剂，乙酸阿比特龙酯（其中的活性代谢产物是阿比特龙）已显示可改善去势抵抗性前列腺癌（CRPC）患者的总体生存-在未接受过化疗的患者和以前接受过多西他赛治疗的患者中。此外，阿比特龙的临床成功表明，以前被认为是雄激素非依赖性疾病的CRPC仍然至少部分地由雄激素驱动。更重要的是，阿比特龙是一种“混杂”药物，可与许多靶标相互作用，从而决定其临床益处和不良反应。除了CYP17抑制作用外，阿比特龙还可以作为雄激素受体的拮抗剂并抑制3β-羟基类固醇脱氢酶，这两种作用可能会导致其抗肿瘤作用。但是，对CYP17，CYP11B1和一组肝CYP酶的17α-羟化酶活性的抑制会导致不良反应和毒性，包括继发性盐皮质激素过量。阿比特龙也与心脏疾病的发生率增加有关。在这种情况下，迫切需要开发新的CYP17抑制剂作为另一道防线。为了获得增强的临床益处，正在探索新的策略，包括选择性抑制CYP17的C17,20-裂合酶活性和在不同点影响雄激素合成和信号传导的多目标策略。临床前数据支持其中一些策略-包括药物orteronel，VT-464和galeterone-并正在临床中进行探索。

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