Imperial College London
Alternate

ProfessorCharlotteBevan

Faculty of Medicine, Department of Surgery & Cancer

Professor of Cancer Biology
 
 
 
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Contact

 

charlotte.bevan Website

 
 
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Assistant

 

Mrs Suzy Ford +44 (0)20 7594 2135

 
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Location

 

139ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Dart:2018:10.1158/1535-7163.MCT-18-0037,
author = {Dart, DA and Kandil, S and Tommasini-Ghelfi, S and Serrano, de Almeida G and Bevan, CL and Jiang, W and Westwell, AD},
doi = {10.1158/1535-7163.MCT-18-0037},
journal = {Molecular Cancer Therapeutics},
pages = {1846--1858},
title = {Novel trifluoromethylated enobosarm analogues with potent anti-androgenic activity in vitro and tissue selectivity in vivo},
url = {http://dx.doi.org/10.1158/1535-7163.MCT-18-0037},
volume = {17},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Prostate cancer often develops anti-androgen resistance, possibly via androgen receptor (AR) mutations which change antagonists to agonists. Novel therapies with increased anticancer activity, whilst overcoming current drug resistance are urgently needed. Enobosarm has anabolic effects on muscle and bone whilst 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 to enobosarm, and are ideal candidates for further development for prostate cancer therapy with potentially fewer side effects.
AU  - Dart,DA
AU  - Kandil,S
AU  - Tommasini-Ghelfi,S
AU  - Serrano,de Almeida G
AU  - Bevan,CL
AU  - Jiang,W
AU  - Westwell,AD
DO  - 10.1158/1535-7163.MCT-18-0037
EP  - 1858
PY  - 2018///
SN  - 1535-7163
SP  - 1846
TI  - Novel trifluoromethylated enobosarm analogues with potent anti-androgenic activity in vitro and tissue selectivity in vivo
T2  - Molecular Cancer Therapeutics
UR  - http://dx.doi.org/10.1158/1535-7163.MCT-18-0037
UR  - https://www.ncbi.nlm.nih.gov/pubmed/29895558
UR  - http://hdl.handle.net/10044/1/61165
VL  - 17
ER  -
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