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Mol Cancer Ther. 2018 Sep;17(9):1846-1858. doi: 10.1158/1535-7163.MCT-18-0037. Epub 2018 Jun 12.

Novel Trifluoromethylated Enobosarm Analogues with Potent Antiandrogenic Activity In Vitro and Tissue Selectivity In Vivo.

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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.
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, Wales, United Kingdom.
Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, Wales, United Kingdom.
Contributed equally


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.

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