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Novel androgen receptor antagonist identified by structure-based virtual screening, structural optimization, and biological evaluation.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-21 , DOI: 10.1016/j.ejmech.2020.112156 Qin Tang 1 , Weitao Fu 1 , Minkui Zhang 1 , Ercheng Wang 1 , Lvhu Shan 2 , Xin Chai 1 , Jinping Pang 1 , Xuwen Wang 1 , Xiaohong Xu 2 , Lei Xu 3 , Dan Li 1 , Rong Sheng 1 , Tingjun Hou 1
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-21 , DOI: 10.1016/j.ejmech.2020.112156 Qin Tang 1 , Weitao Fu 1 , Minkui Zhang 1 , Ercheng Wang 1 , Lvhu Shan 2 , Xin Chai 1 , Jinping Pang 1 , Xuwen Wang 1 , Xiaohong Xu 2 , Lei Xu 3 , Dan Li 1 , Rong Sheng 1 , Tingjun Hou 1
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Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa), and therefore it has been regarded as the most important therapeutic target for both hormone-sensitive prostate cancer (HSPC) and advanced PCa. In this study, a novel hit (C18) with IC50 of 2.4 μM against AR transcriptional activity in LNCaP cell was identified through structure-based virtual screening based on molecular docking and free energy calculations. The structure-activity relationship analysis and structural optimization of C18 resulted in the discovery of a structural analogue (AT2), a more potent AR antagonist with 16-fold improved anti-AR potency. Further assays indicated that AT2 was capable of effectively inhibiting the transcriptional function of AR and blocking the nuclear translocation of AR like the second-generation AR antagonists. The antagonists discovered in this study may be served as the promising lead compounds for the development of AR-driven PCa therapeutics.
中文翻译：
通过基于结构的虚拟筛选，结构优化和生物学评估确定了新型雄激素受体拮抗剂。
雄激素受体（AR）在前列腺癌（PCa）的发展中起着重要作用，因此，它已被视为激素敏感性前列腺癌（HSPC）和晚期PCa的最重要治疗靶标。在这项研究中，通过基于分子对接和自由能计算的基于结构的虚拟筛选，鉴定了针对LNCaP细胞中AR转录活性的IC50为2.4μM的新型命中点（C18）。C18的结构活性关系分析和结构优化导致发现了结构类似物（AT2），这是一种更有效的AR拮抗剂，抗AR效力提高了16倍。进一步的分析表明，像第二代AR拮抗剂一样，AT2能够有效抑制AR的转录功能并阻断AR的核易位。
更新日期：2020-02-21
中文翻译：
通过基于结构的虚拟筛选，结构优化和生物学评估确定了新型雄激素受体拮抗剂。
雄激素受体（AR）在前列腺癌（PCa）的发展中起着重要作用，因此，它已被视为激素敏感性前列腺癌（HSPC）和晚期PCa的最重要治疗靶标。在这项研究中，通过基于分子对接和自由能计算的基于结构的虚拟筛选，鉴定了针对LNCaP细胞中AR转录活性的IC50为2.4μM的新型命中点（C18）。C18的结构活性关系分析和结构优化导致发现了结构类似物（AT2），这是一种更有效的AR拮抗剂，抗AR效力提高了16倍。进一步的分析表明，像第二代AR拮抗剂一样，AT2能够有效抑制AR的转录功能并阻断AR的核易位。
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