Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, Wales, United Kingdom.
Androgen Signaling Laboratory, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Mol Cancer Ther. 2018 Sep;17(9):1846-1858. doi: 10.1158/1535-7163.MCT-18-0037. Epub 2018 Jun 12.
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 -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. , 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. , 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 the - 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. .
前列腺癌常发生抗雄激素耐药，可能通过雄激素受体（AR）突变，将拮抗剂变为激动剂。迫切需要具有增加抗癌活性而克服当前耐药性的新型疗法。恩诺博沙姆对肌肉和骨骼具有合成代谢作用，而对前列腺没有影响。在这里，我们描述了新型化学修饰的恩诺博沙姆类似物的活性。在恩诺博沙姆的环 B 中合理地添加 -三氟甲基，极大地改变了它们的活性、药代动力学和组织分布特征。这些化学结构修饰导致 AR 结合亲和力的提高，通过增加 AR 螺旋 12 附近的分子占据体积。其中，类似物 SK33 和 SK51 表现出非常有效的抗雄激素活性，使用 LNCaP/AR-Luciferase 细胞监测，其中生长、PSA 和荧光素酶活性被用作 AR 活性测量。与恩诺博沙姆相比，这些化合物在 LNCaP 模型中分别比比卡鲁胺和 100 倍更有效。这些化合物在具有获得性比卡鲁胺耐药性的 LNCaP/BicR 细胞中也具有活性。使用 AR-Luc 报告小鼠，这些药物在前列腺和其他 AR 表达组织（如睾丸、精囊和大脑）中显示出强烈的 AR 抑制活性。这些化合物不会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征。这些化合物在 -缺失模型中也具有活性。与恩诺博沙姆相比，SK33 和 SK51 的活性谱明显不同且增强，是前列腺癌治疗的进一步开发的理想候选药物，潜在副作用更少。
