MP62-01 TARGETING THE DNA BINDING DOMAIN OF THE ANDROGEN RECEPTOR: EFFICACY OF PROSTATE CANCER COMPOUND WITH NOVEL MECHANISM OF ACTION (2016)

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I1 Apr 2016MP62-01 TARGETING THE DNA BINDING DOMAIN OF THE ANDROGEN RECEPTOR: EFFICACY OF PROSTATE CANCER COMPOUND WITH NOVEL MECHANISM OF ACTION Hendrik Borgmann, Kush Dalal, Eliana Beraldi, Artem Cherkasov, Paul Rennie, and Martin Gleave Hendrik BorgmannHendrik Borgmann More articles by this author , Kush DalalKush Dalal More articles by this author , Eliana BeraldiEliana Beraldi More articles by this author , Artem CherkasovArtem Cherkasov More articles by this author , Paul RenniePaul Rennie More articles by this author , and Martin GleaveMartin Gleave More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.909AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In castration-resistant prostate cancer, resistance to conventional treatments targeting the ligand binding domain of the androgen receptor (AR) occur inevitably, prompting the need to develop small molecules with a different binding location on the AR and novel mechanism of action. Recently, we identified a pocket on the AR-DNA binding domain (DBD) protein surface with potential as an alternative drug-target site. Here, we present preclinical data on an AR-DBD specific compound and its inhibitory effects across multiple prostate cancer cell lines in vitro and in vivo. METHODS We tested the effect of VPC-14449 on cell growth of the hormone sensitive cell line LNCaP, the Enzalutamide resistant cell line MR49C and the AR Variant driven cell line 22Rv1 by MTS assay and compared to enzalutamide. Moreover, we assessed the effect of VPC-14449 on AR transcriptional activity of these cell lines using luciferase reporter assay. In castrated mice, change in volume of LNCaP tumour xenografts and serum PSA levels was determined after compound treatment over 4 weeks. RESULTS Treatment with VPC-14449 led to dose-dependent cell growth inhibition in all three cell lines. Enzalutamide inhibited cell growth of LNCaP, but not 22Rv1 and MR49C cells for which an agonistic effect of Enzalutamide was observed at high compound concentrations. VPC-14449 blocked transcriptional activity of the AR in LNCaP, MR49C and 22Rv1 cell lines. Finally, the compound suppressed the growth of LNCaP tumor xenografts by 68% (p<0.01) and serum PSA levels by 81% (p<0.01) in mice at week 4. CONCLUSIONS The developed AR-DBD inhibiting compound showed excellent efficacy in preclinical studies across multiple prostate cancer cell lines in vitro and in vivo. AR-DBD inhibiting compounds may complement the armamentarium of drugs as effective non-cross-resistant treatment of castration-resistant prostate cancer. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e812 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Hendrik Borgmann More articles by this author Kush Dalal More articles by this author Eliana Beraldi More articles by this author Artem Cherkasov More articles by this author Paul Rennie More articles by this author Martin Gleave More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...