MP66-08 DUAL PATHWAY INHIBITION IN PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2015MP66-08 DUAL PATHWAY INHIBITION IN PROSTATE CANCER Eugine Lee, Susan Ha, and Susan Logan Eugine LeeEugine Lee More articles by this author , Susan HaSusan Ha More articles by this author , and Susan LoganSusan Logan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2361AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Androgen deprivation therapy is the mainstay of aggressive prostate cancer treatment, but can result in drug resistance and disease recurrence. Our studies show that small molecule inhibition of nuclear β-catenin can inhibit transcription of the androgen receptor (AR) by decreasing β-catenin occupancy on the AR promoter. Such an approach that targets AR transcription and lowers AR levels independent of hormone ligand action is important in light of recent studies showing that AR splice variants lacking the ligand-binding domain can still promote transcription. We recently showed that a small molecule inhibitor of nuclear β-catenin, an oxazole compound called inhibitor of beta-catenin responsive transcription-3 (iCRT3), can inhibit both AR and β-catenin action, resulting in prostate cell and tumor growth inhibition. Although promising, iCRT3 was not stable enough for systemic use and its effect was dependent on direct injection into tumors. METHODS To identify new inhibitors of nuclear β-catenin with improved pharmacokinetic properties, we conducted a screen in LNCaP-abl prostate cancer cells at the Rockefeller University High-Throughput Screening Resource Center. We screened 10,353 compounds that maximize “chemical diversity space” intended to accelerate the hit-to-lead process and assayed a Wnt/β-catenin reporter activity followed by a secondary screen assaying AR reporter gene activity. RESULTS We identified 55 compounds that reproducibly inhibited the Wnt/β-catenin reporter gene and AR reporter gene, underscoring the strength of our approach to target the AR and Wnt/β-catenin pathways. We recently determined the IC50 value of these compounds by validating their ability to inhibit the Wnt/β-catenin reporter gene using concentrations ranging from 20 micromolar to 39 nanomolar. Four compounds inhibited transcription at a concentration of 1.25 micromolar and 16 showed inhibition into the nanomolar range. Among these, 11 compounds showed no toxicity in 293 cells but were toxic to LNCaP-abl cells. The characteristics of these 11 compounds also satisfied the Lipinski rules used to evaluate the potential of chemical compounds for drug development. CONCLUSIONS Our studies underscore the potential of small molecule inhibitors of nuclear β-catenin to target both the AR and Wnt/β-catenin pathways, thus killing prostate cancer cells. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e818-e819 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eugine Lee More articles by this author Susan Ha More articles by this author Susan Logan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...