Endocrine Abstracts (2016) 42 OC3 | DOI: 10.1530/endoabs.42.OC3

Novel trifluoromethylated enobosarm analogues show very potent antiandrogen activity in prostate cancer cells, and cells with acquired bicalutamide resistance whilst maintaining tissue selectivity in vivo

Alwyn Dart1, Sahar Kandil3, Serena Tommasini-Ghelfi2, Charlotte Bevan2, Wenguo Jiang1 & Andrew D. Westwell3


1The Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, Wales, UK; 2Androgen Signalling Laboratory, Department of Surgery & Cancer, Imperial College London, South Kensington Campus, London, W12 0NN, UK; 3School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, CF10 3NB Cardiff, Wales, UK


Prostate cancer often develops anti-androgen resistance, possibly via AR mutations which change AR antagonists to agonists. There is an urgent need for novel therapies which ideally show increased anticancer activity, whilst overcoming current drug resistance. Enobosarm has anabolic effects on muscle and bone tissues whilst having no effect on the prostate – often used to combat cachexia in advanced lung cancer. Here we describe the activity of novel chemically modified Enobosarm analogues. The addition of bis-trifluoromethyl groups, profoundly modified their pharmacokinetics and pharmacodynamic properties. These chemical structural modifications appeared changed their AR ligand binding site affinities – by increasing the molecular occupational volume near the AR helix 12, impeding the agonist conformation. In vitro, the analogues SK33 and SK51 showed very potent antiandrogen activity, monitored using LNCaP/AR-Luciferase cells where growth, PSA and luciferase were used as a measure of AR activity. These drugs were 10x more potent than bicalutamide and 100x more potent than the parental Enobosarm. The compounds were also active in LNCaP cells with acquired bicalutamide resistance – cells normally showing active proliferation in response to bicalutamide. In vivo, using the AR-Luc reporter mice, these drugs showed potent activity in the prostate and several other AR-expressing tissues e.g. testes, seminal vesicles and brain. These agents did not inhibit AR activity in the skeletal muscle, spleen and bone – thus indicating a selective inhibitory profile – Selective Androgen Receptor Modulatory (SARM) activity. SK33 and SK51 have significantly different activity profiles to enobosarm, and are ideal candidates for prostate cancer therapy as they have increased efficacy and potentially fewer side effects.

Funding: Cancer Research UK.

Presenting Author: Alwyn Dart, The Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, Wales, UK. Email: dartd@cardiff.ac.uk

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