Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Novel trifluoromethylated enobosarm analogues with potent antiandrogenic activity in vitro and tissue selectivity in vivo

Dart, Dafydd Alwyn, Kandil, Sahar, Westwell, Andrew, Jiang, Wen Guo, Tommasini-Ghelfi, Serena, Bevan, Charlotte and Almeida, Gilberto Serrano de 2018. Novel trifluoromethylated enobosarm analogues with potent antiandrogenic activity in vitro and tissue selectivity in vivo. Molecular Cancer Therapeutics 17 (9) , pp. 1846-1858. 10.1158/1535-7163.MCT-18-0037

[img]
Preview
PDF - Accepted Post-Print Version
Download (6MB) | Preview

Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Pharmacy
Publisher: American Association for Cancer Research
ISSN: 1535-7163
Date of First Compliant Deposit: 27 June 2018
Date of Acceptance: 7 June 2018
Last Modified: 20 Oct 2019 11:25
URI: http://orca-mwe.cf.ac.uk/id/eprint/112257

Citation Data

Cited 1 time in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics