Prostate cancer often develops antiandrogen resistance, possibly via androgen receptor (AR) mutations, which change antagonists to agonists. Novel therapies with increased anticancer activity, while overcoming current drug resistance are urgently needed. Enobosarm has anabolic effects on muscle and bone while having no effect on the prostate. Here, we describe the activity of novel chemically modified enobosarm analogues. The rational addition of bis‐trifluoromethyl groups into ring B of enobosarm, profoundly modified their activity, pharmacokinetic and tissue distribution profiles. These chemical structural modifications resulted in an improved AR binding affinity—by increasing the molecular occupational volume near helix 12 of AR. In vitro, the analogues SK33 and SK51 showed very potent antiandrogenic activity, monitored using LNCaP/AR‐Luciferase cells where growth, PSA and luciferase activity were used as AR activity measurements. These compounds were 10-fold more potent than bicalutamide and 100-fold more potent than enobosarm within the LNCaP model. These compounds were also active in LNCaP/BicR cells with acquired bicalutamide resistance. In vivo, using the AR‐Luc reporter mice, these drugs showed potent AR inhibitory activity in the prostate and other AR‐expressing tissues, e.g., testes, seminal vesicles, and brain. These compounds do not inhibit AR activity in the skeletal muscle, and spleen, thus indicating a selective tissue inhibitory profile. These compounds were also active in vivo in the Pb-Pten deletion model. SK33 and SK51 have significantly different and enhanced activity profiles compared with enobosarm and are ideal candidates for further development for prostate cancer therapy with potentially fewer side effects. Mol Cancer Ther; 17(9); 1846–58. ©2018 AACR.

中文翻译：

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具有有效体外抗雄激素活性和体内组织选择性的新型三氟甲基化 Enobosarm 类似物。

前列腺癌通常会产生抗雄激素耐药性，可能是通过雄激素受体 (AR) 突变，将拮抗剂变为激动剂。迫切需要具有增强抗癌活性同时克服当前耐药性的新疗法。Enobosarm 对肌肉和骨骼有合成代谢作用，而对前列腺没有影响。在这里，我们描述了新型化学修饰的 enobosarm 类似物的活性。将双三氟甲基合理添加到 enobosarm 的 B 环中，极大地改变了它们的活性、药代动力学和组织分布特征。这些化学结构修饰通过增加 AR 螺旋 12 附近的分子占据体积来提高 AR 结合亲和力。在体外，类似物 SK33 和 SK51 显示出非常有效的抗雄激素活性，使用 LNCaP/AR-荧光素酶细胞监测，其中生长、PSA 和荧光素酶活性用作 AR 活性测量。在 LNCaP 模型中，这些化合物的效力比比卡鲁胺强 10 倍，比 enobosarm 强 100 倍。这些化合物在具有获得性比卡鲁胺耐药性的 LNCaP/BicR 细胞中也有活性。在体内，使用 AR-Luc 报告基因小鼠，这些药物在前列腺和其他表达 AR 的组织（例如睾丸、精囊和大脑）中显示出有效的 AR 抑制活性。这些化合物不抑制骨骼肌和脾脏中的 AR 活性，因此表明具有选择性的组织抑制特性。这些化合物在体内 Pb-Pten 缺失模型中也具有活性。与 enobosarm 相比，SK33 和 SK51 具有显着不同和增强的活性谱，是进一步开发前列腺癌治疗的理想候选者，副作用可能更少。摩尔癌症治疗; 17(9); 1846-58 年。©2018 AACR。